Biphenyl derivatives

ABSTRACT

A biphenyl derivative represented by the following formula (I) or a pharmacologically acceptable salt thereof:                    
     wherein R 1 , R 2 , R 3 , R 4 , and R 5  are defined in the specification, is clinically useful for treating and ameliorating mental disorders such as cerebrovascular disorder, aggressive behavior due to senile dementia, mental excitation, poriomania, delirium, hallucination, hyperkinesia, schizophrenia, emotional disturbance, depression, neurosis, psychophysiologic disorder and anxiety neurosis. The compounds exhibit dopamine 2 receptor antagonism and/or serotonin 2 receptor antagonism.

This application is a divisional of application Ser. No. 08/855,790,filed on May 12, 1997 now U.S. Pat. No. 5,849,912, which is a Rule 62Continuation of application Ser. No. 08/409,084, filed Mar. 22, 1995,now abandoned, the entire contents of which are hereby incorporated byreference.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to biphenyl derivatives. Moreparticularly, it relates to biphenyl derivatives which exhibit dopamine2 receptor antagonism and/or serotonin 2 receptor antagonism and whichare clinically useful as therapeutic and ameliorative agents for mentaldisorders such as cerebrovascular disorder, aggressive behavior due tosenile dementia, mental excitation, poriomania, delirium, hallucination,hyperkinesia, schizophrenia, emotional disturbance, depression,neurosis, psychophysiologic disorder and anxiety neurosis.

2. Description of the Related Art

Mental disorders such as cerebrovascular disorder and dementia arefrequently found in the aged, which becomes a significant problem withthe approach of an aging society. In many cases, these diseases areaccompanied with mental and/or behavior disorders which specificallyappear as delirium, hallucination, hyperkinesia, poriomania, mentalexcitation or other sign or symptom. These signs and symptoms not onlyhave an adverse effect on a patient himself, but also necessitateeveryday care, imposing a heavy burden on the people around the patient.Under these circumstances, the development of a highly clinically usefulmedicine which can treat the above mental disorders medically has beenexpected not only by patients and their families, but also socially.

Only Tiapride is now authorized as a therapeutic and ameliorative agentfor the above diseases, and Haloperidol which is an antischizophrenicdrug is also used, though the diseases are not included in theindications for which the drug is efficacious.

As novel compounds having an antipsychotic activity, benzisothiazolederivatives and benzisoxazole derivatives are disclosed in EuropeanPatent Publication-A No. 196132, and pyridine derivatives are disclosedin U.S. Pat. No. 5,021,421.

Tiapride and haloperidol are medicines exhibiting dopamine 2 (D₂)receptor antagonism. A medicine of this type has a problem of causingextrapyramidal syndrome including dystonia (hypermyotonia or musclehypotonia), hypokinesis (akinesis), hyperkinesia (abnormal movement) andso forth as an adverse reaction, though the medicine is clinicallyefficacious.

Risperidone which is a representative example of the benzisoxazolederivative disclosed in the above European Patent Publication-A No.196132 is authorized as an antischizophrenic drug in the United States,the United Kingdom and Canada. However, this drug is problematic in thatblood-pressure drop occurs as an adverse reaction owing to the high α₁blocking activity of the drug and that the QT_(C) interval inelectro-cardiogram is lengthened to induce arrhythmia, being undesirableparticularly when administered to a patient of advanced age.

The pyridine derivative disclosed in the above U.S. Pat. No. 5,021,421also exhibits potent dopamine 2 receptor antagonism and is thereforefeared to cause extrapyramidal syndrome like Tiapride or Haloperidol.Further, the pyridine derivative has not been used clinically as yet, sothat its safeness in prolonged application is not apparent.

As described above, there has not been found any therapeutic andameliorative agent for mental disorders such as cerebrovasculardisorder, aggressive behavior due to senile dementia, mental excitation,poriomania, delirium, hallucination, hyperkinesia, schizophrenia,emotional disturbance, depression, neurosis, psychophysiologic disorderand anxiety neurosis, which has high clinical usefulness and isexcellent in safeness.

DISCLOSURE OF THE INVENTION

3. Summary of the Invention

An object of the present invention is to provide novel biphenylderivatives and pharmacologically acceptable salts thereof which exhibitdopamine 2 receptor antagonism and/or serotonin 2 receptor antagonism,are clinically useful as therapeutic and ameliorative agents for mentaldiseases, is improved in the disadvantageous extrapyramidal syndrome ascompared with dopamine 2 receptor antagonists of the prior art such asTiapride and Haloperidol, and is freed from the adverse reactions causedby the above benzisoxazole derivative (such as Risperidone), forexample, blood-pressure drop and induction of arrhythmia.

Another object of the present invention is to provide processes for thepreparation of the biphenyl derivatives described above.

Another object of the present invention is to provide phenylpiperazinederivatives and salts thereof which are useful as intermediates in theproduction of the biphenyl derivatives and pharmacologically acceptablesalts thereof described above.

The present inventors have extensively studied to find an extremely safeand useful therapeutic and ameliorative agent for mental disorders whichexhibits dopamine 2 receptor antagonism and does not causeextrapyramidal syndrome, blood-pressure drop, induction of arrhythmia orother adverse reaction, with their attention being paid to compoundsexhibiting both dopamine 2 receptor antagonism and serotonin 2 receptorantagonism. As a result, they have found that specific biphenylderivatives and pharmacologically acceptable salts thereof which arenovel compounds have an excellent therapeutic and ameliorative effect onmental disorders and are excellent in safeness, solving the aboveproblems. The present invention has been accomplished on the basis ofthis finding.

Thus, the present invention provides a biphenyl derivative representedby the following formula (I) or a pharmacologically acceptable saltthereof:

wherein R¹ represents a hydrogen atom, a halogen atom, a hydroxyl group,an amino group, a cyano group, a pyrrolidyl group, a lower alkyl group,a halogenated lower alkyl group, a cyano lower alkyl group, a hydroxylower alkyl group, an amino lower alkyl group, a cycloalkyl group, acycloalkylalkyl group, a lower alkoxyalkyl group, a heteroarylalkylgroup, a halogenated heteroarylalkyl group, a lower acylalkyl group, aheteroarylalkoxyalkyl group, a cycloalkyloxyalkyl group, anaralkyloxyalkyl group, an alkenyloxyalkly group, a loweralkoxycarbonylalkyl group, a lower alkoxyalkoxyalkyl group, anarylhydroxyalkyl group, a hydroxyheteroarylalkyl group, acycloalkylalkoxyalkyl group, an alkonyl group, a halogenated alkenylgroup, an alkynyl group, an aralkyl group, a halogenated aralkyl group,a hydroxyaralkyl group, a halogenated hydroxylminoaralkyl group, a loweralkoxy group, a halogenated lower alkoxy group, a lower alkoxyalkoxygroup, an aryl group, a hydroxyaryl group, a halogenated aryl group, alower alkoxyaryl group, a heteroaryl group, a hydroxyheteroaryl group, ahalogenated heteroaryl group, a lower alkoxyheteroaryl group, a formylgroup, a lower acyl group, an aromatic acyl group, a heteroaromatic acylgroup, an aralkylcarbonyl group, a cycloalkylalkylcarbonyl group, aheteroarylalkylcarbonyl group, a halogenated aralkylcarbonyl group, alower alkoxycarbonyl group, an aryloxycarbonyl group, a lower alkylaminogroup, a lower alkylsulfonylamino group, a halogenated loweralkylsulfonylamino group, an arylsulfonylamino group, a halogenatedarylsulfonylamino group, an aralkylsulfonyl amino group, a cycloethergroup, a lower cyclic acetal group, a lower cyclic thioacetal group, alower alkylsulfinyl group, an arylsulfinyl group, an aralkylsulfinylgroup, a heteroarylsulfinyl group, a lower alkylsulfonyl group, anarylsulfonyl group, an aralkylsulfonyl group, a heteroarylsulfonylgroup, a cycloalkylsulfonyl group, an aminosulfonyl group, a loweralkylaminosulfonyl group, an arylaminosulfonyl group, apyrrolidylsulfonyl group, a cycloalkylaminosulfonyl group, a halogenatedlower alkylsulfonyl group, a halogenated aryloxy lower alkylsulfonylgroup or a cyano lower alkylsulfonyl group;

R² and R³ may be the same or different from each other and eachrepresents a hydrogen atom, a halogen atom, a cyano group, a hydroxylgroup, a lower alkyl group, a halogenated lower alkyl group, a loweralkoxyalkyl group, a lower alkoxy group or a halogenated lower alkoxygroup;

R⁴ represents a hydrogen atom, a halogen atom, a lower alkyl group, ahydroxy lower alkyl group, a hydroxyiminomethyl group or a formyl group;

R⁵ represents a hydrogen atom, a lower alkyl group, a halogenated loweralkyl group, a hydroxy lower alkyl group, a heteroarylalkyl group, anaralkyl group, a lower alkoxycarbonyl group or an aryloxycarbonyl group;and

n is 0 or an integer of 1 to 3.

Among the biphenyl derivatives and the pharmacologically acceptablesalts thereof described above, those represented by the followingformula (II) and the pharmacologically acceptable salts thereof arepreferable:

wherein R¹, R², R³, R⁴, R⁵ and n are each as defined above.

Among the biphenyl derivatives and the pharmacologically acceptablesalts thereof described above, those represented by the above formula(I), wherein R¹ is a halogenated lower alkyl group or a loweralkylsulfonylamino group; R² is a halogen atom or a lower alkoxy group;R³ is a halogen atom, a lower alkyl group or a cyano group; R⁴ is ahydrogen atom or a halogen atom; R is a hydrogen atom, a lower alkylgroup or a hydroxy lower alkyl group; and n is 0, and thepharmacologically acceptable salts thereof are particularly preferable.

Among the biphenyl derivatives and the pharmacologically acceptablesalts thereof described above, those represented by the followingformula (II′) and the pharmacologically acceptable salts thereof areparticularly preferable:

wherein R¹ represents a hydrogen atom, a halogen atom, a hydroxyl group,an amino group, a lower alkyl group, a halogenated lower alkyl group, alower alkoxy group, a halogenated lower alkoxy group, a loweralkoxyalkyl group, a lower alkoxyalkoxy group, an aryl group, an aralkylgroup, a heteroaryl group, a heteroarylalkyl group, a halogenatedheteroarylalkyl group, a cyano lower alkyl group, a hydroxy lower alkylgroup, an amino lower alkyl group, a lower alkoxycarbonyl group, anaryloxycarbonyl group, a cyano group, a formyl group, a lower acylgroup, an aralkylcarbonyl group, a cycloether group, an alkenyl group,an alkynyl group, a lower alkylsulfinyl group, a lower alkylsulfonylgroup, a lower alkylaminosulfonyl group, an arylaminosulfonyl group, alower alkylsulfonylamino group, a halogenated lower alkylsulfonylamniogroup or an arylsulfonylamino group;

R² and R³ may be the same or different from each other and eachrepresents a hydrogen atom, a halogen atom, a lower alkyl group, ahalogenated lower alkyl group, a lower alkoxy group, a halogenated loweralkoxy group or a cyano group;

R⁴ represents a hydrogen atom or a halogen atom;

R⁵ represents a hydrogen atom, a lower alkyl group, a halogenated loweralkyl group, a hydroxy lower alkyl group, a lower alkoxycarbonyl groupor an aryloxycarbonyl group; and

n is 0 or an integer of 1 to 3.

Further, the present invention provides a therapeutic and ameliorativeagent for a mental disorder, which comprises the above-mentionedbiphenyl derivative of the formula (I) or the pharmacologicallyacceptable salt thereof as an active ingredient.

Furthermore, the present invention provides a pharmacologicalcomposition which comprises a therapeutically or ameliorativelyeffective amount of the above-mentioned biphenyl derivative of theformula (I) or the pharmacologically acceptable salt thereof, and apharmacologically acceptable vehicle; an use of the above-mentionedbiphenyl derivative of the formula (I) or the pharmacologicallyacceptable salt thereof for the making of a medicament for treating orameliorating a disease against which dopamine 2 receptor antagonismand/or serotonin 2 receptor antagonism is efficacious; and a method fortreating or ameliorating a disease which comprises administering apharmaceutically effective amount of the above-mentioned biphenylderivative of the formula (I) or the pharmacologically acceptable saltthereof to a patient suffering from a disease against which dopamine 2receptor antagonism and/or serotonin 2 receptor antagonism isefficacious.

In addition, the present invention provides processes for the productionof the above-mentioned biphenyl derivatives, which will be specificallydescribed below.

The present invention provides a phenylpiperazine derivative representedby the following general formula (XXVII) or a salt thereof:

wherein R² represents a hydrogen atom, a halogen atom, a cyano group, ahydroxyl group, a lower alkyl group, a halogenated lower alkyl group, alower alkoxyalkyl group, a lower alkoxy group or a halogenated loweralkoxy group; R¹⁰ represents a halogenated lower alkyl group, a hydroxylower alky group, a halogen atom, a lower alkylsulfonyl group, a loweralkoxycarbonyl group, a carboxyl group, an alkenyl group, a(pyridylthio)carbonyl group or a lower acyl group; and R¹¹ represents ahydrogen atom, a lower alkyl group, a halogenated lower alkyl group, ahydroxy lower alkyl group, a tri(lower alkyl)silyloxy lower alkyl group,a heteroarylalkyl group, an aralkyl group, a lower alkoxycarbonyl group,an aryloxycarbonyl group or an amino-protecting group.

Among the phenylpiperazine derivatives and salts thereof describedabove, those represented by the above formula (XXVII), wherein R² is asdefined above: R¹⁰ represents a halogenated lower alkyl group or ahydroxy lower alkyl group; and R¹¹ represents a hydrogen atom, a hydroxylower alkyl group or an amino-protecting group, and salts thereof arepreferable.

Among the phenylpiperazine derivatives and salts thereof describedabove, those represented by the above formula (XXVII), wherein R²represents a hydrogen atom, a halogen atom, a lower alkyl group, ahalogenated lower alkyl group, a lower alkoxy group, a halognated loweralkoxy group or a cyano group; R¹⁰ represents a halogenated lower alkylgroup or a hydroxy lower alkyl group; and R¹¹ represents a hydrogenatom, a hydroxy lower alkyl group or an amino-protecting group, andsalts thereof are particularly preferable.

Further scope and applicability of the present invention will becomeapparent from the detailed description given hereinafter. However, itshould be understood that the detailed description and specificexamples, while indicating preferred embodiments of the invention, aregiven by way of illustration only, since various changes andmodifications within the spirit and scope of the invention will becomeapparent to those skilled in the art from this detailed description.

DETAILED DESCRIPTION OF THE INVENTION

With respect to the above definition of the above formulas, particularexamples of the halogen atom include chlorine atom, fluorine atom,bromine atom and iodine atom, among which fluorine atom and chlorineatom are preferable. Particular examples of the lower alkyl groupinclude alkyl groups having 1 to 6 carbon atoms, such as methyl group,ethyl group, n-propyl group, i-propyl group, n-butyl group, i-butylgroup, t-butyl group, pentyl group and hexyl group; the halogenatedlower alkyl group is a lower alkyl group described above in which atleast one halogen atom substitutes for the hydrogen atom, and particularexamples thereof include fluoromethyl group, difluoromethyl group,trifluoromethyl group, fluoroethyl group, fluoropropyl group,chlorobutyl group and chloropentyl group; the lower alkoxy group is alower alkyl group described above to which an oxygen atom is bonded, andparticular examples thereof include methoxy group, ethoxy group andpropoxy group; the halogenated lower alkoxy group is a lower alkoxygroup described above in which at least one halogen atom substitutes forthe hydrogen atom, and particular examples thereof include fluoromethoxygroup and chloroethoxy group; the lower alkoxyalkyl group is a loweralkyl group described above in which a lower alkoxy group substitutesfor the hydrogen atom, and particular examples thereof includemethoxymethyl group, methoxyethyl group and methoxypropyl group; thelower alkoxyalkoxy group is a lower alkoxy group described above inwhich a lower alkoxy group substitutes for the hydrogen atom bonded tothe carbon atom, and particular examples thereof include methoxymethoxygroup, methoxyethoxy group and methoxypropoxy group; particular examplesof the aryl group include phenyl group, tolyl group (—C₆H₄CH₃), xylylgroup [—C₆(CH₃)₂], methoxyphenyl group, chlorophenyl group, bromophenylgroup, fluorophenyl group, nitrophenyl group and cyanophenyl group;particular examples of the aralkyl group include benzene group,methylbenzyl group, phenethyl group and phenylpropyl group; particularexamples of the heteroaryl group include thienyl group, furanyl group,pyranyl group, imidazolyl group, thiazolyl group, pyridyl group andpyrazyl group; particular examples of the heteroarylalkyl group includethienylmethyl group, furfuryl group, imidazolylmethyl group,thiazolylmethyl group, pyridylmethyl group and pyrazylmethyl group; thehalogenated heteroarylalkyl group is a heteroarylalkyl group describedabove in which at least one halogen atom substitutes for the hydrogenatom; the cyano lower alkyl group is a lower alkyl group described abovein which at least one cyano group substitutes for the hydrogen atom; thehydroxy lower alkyl group is a lower alkyl group described above inwhich at least one hydroxyl group substitutes for the hydrogen atom; theamino lower alkyl group is a lower alkyl group described above in whichat least one amino group substitutes for the hydrogen atom; the loweralkoxycarbonyl group is a lower alkoxy group described above to which acarbonyl group is bonded, and particular examples thereof includemethoxy carbonyl group and ethoxycarbonyl group; the aryloxycarbonylgroup is an aryl group described above to which an oxygen atom having acarbonyl group bonded thereto is bonded, and particular examples thereofinclude phenoxycarbonyl group, tolyloxycarbonyl group andxylyloxycarbonyl group; the lower acyl group is a lower alkyl groupwhich has 1 to 6 carbon atoms and to which a carbonyl group is bonded,and particular examples thereof include acetyl group, propionyl group,butyryl group and valeryl group; particular examples of the aromaticacyl group include benzoyl group, anisoyl group, nitrobenzoyl group,chlorobenzoyl group, cyanobenzoyl group, toluoyl group and xyloyl group;particular examples of the cycloether group include tetrahydrofuranylgroup and tetrahydropyranyl group; particular examples of the alkenylgroup include vinyl group, propenyl group and butenyl group; aparticular example of the alkynyl group includes propargyl group; thelover alkylsulfinyl group is a lower alkyl group described above towhich a sulfinyl group (—SO—) is bonded, and particular examples thereofinclude methanesulfinyl group and ethanesulfinyl group; the loweralkylsulfonyl group is a lower alkyl group described above to which asulfonyl group (—SO₂—) is bonded, and particular examples thereofinclude methanesulfonyl group and ethanesulfonyl group; the loweralkylaminosulfonyl group is an aminosulfonyl group (>NSO₂—) in which theN atom has one lower alkyl grouD described above and one hydrogen atombonded thereto, or two lower alkyl groups described above bondedthereto, and particular examples thereof include metzhylaminosulfonylgroup and dimethylaminosulfonyl group; thee arylaminosulfonyl group isan aminosulfonyl group in which the N, atom has one aryl group describedabove bonded thereto, or two aryl groups described above bonded thereto,and particular examples thereof include phenylaminosulfonyl group anddiphenylaminosulfonyl group; the lower alkyl sulfonylamino group is alower alkyl group described above to which as sulfonylamino group(—SO₂NH—) is bonded, and particular examples thereof includemethanesulfonylamino group, ethanesulfonylamino group,propanesulfonylamino group and butanesulfonylamino group; thehalogenated lower alkylsulfonylamino group is a lower alkylsulfonylaminogroup described above in which at least one halogen atom substitutes forthe hydrogen atom; the arylsulfonylamino group is an aryl groupdescribed above to which a sulfonylamino group (—SO₂NH—) is bonded, andparticular examples thereof include benzenesulfonylamino group andtoluenesulfonylamino group; the cyclic acetal group is, i.e., analkyldioxymethyl group, and examples thereof include 1,3-dioxolan-2-ylgroup and 1,3-dioxan-2-yl group; and the cyclic thioacetal group is,i.e., an alkyldithiomethyl group, and an example thereof includes1,3-dithian-2-yl group. In particular, it is preferable that R¹ be ahalogenated loover alkyl group or a lower alkylsulfonylamino group, R²be a halogen atom or a lower alkoxy group, R³ be a halogen atom, a loweralkyl group or a cyano group, R⁴ be a hydrogen atom or a halogen atom,R¹ be a hydrogen atom, a lower alkyl group or a hydroxy lower alkylgroup, and n be 0. Further, it is preferable that the substituentrepresented by formula —(CH₂)-piperazine-R⁵ be bonded at the 3-positionof the 1,1′-biphenyl skeleton, though the position of substitution isnot particularly limited.

More specific examples of the biphenyl derivative represented by theabove formula (I) or (II) according to the present invention include thefollowing compounds, though the derivative represented by the aboveformula (I) or (II) is not limited to them:

(1) 1-[3-(2-cyanophenyl)-4-chloro-5-(1-fluoropropyl)]phenylpiperazine,

(2)1-(2-hydroxyethyl)-4-[3-(2-cyanophenyl)-4-chloro-5-(1-fluoropropyl)]phenylpiperazine,

(3) 1-ethyl-4-[3-(2-tolyl)-4-chloro-5-ethoxycarbonyl]phenylpiperazine,

(4) 1-ethyl-4-[3-(2-tolyl)-4-chloro-5-amino]-phenylpiperazine,

(5)1-ethyl-4-[3-(2-tolyl)-4-chloro-5-propanesulfonylamino]phenylpiperazine,

(6)1-ethyl-4-[3-(2-tolyl)-4-chloro-5-ethanesulfonylamino]phenylpiperazine,

(7)1-ethyl-4-[3-(2-tolyl)-4-chloro-5-butanesulfonylamino]phenylpiperazine,

(8)1-methyl-4-[3-(2-cyanophenyl)-4-chloro-5-(1-fluoropropyl)]phenylpiperazine,

(9)1-ethyl-4-[3-(2-cyanophenyl)-4-chloro-5-(1-fluoropropyl)]phenylpiperazine,

(10)1-methyl-4-[3-(2-chlorophenyl)-4-chloro-5-(1-fluoropropyl)]phenylpiperazine,

(11)1-(2-hydroxyethyl)-4-[3-(2-chlorophenyl)-4-chloro-5-(1-fluoropropyl)]phenylpiperazine,

(12)1-ethyl-4-[3-(2-chlorophenyl)-4-chloro-5-(1-fluoropropyl)]phenylpiperazine,

(13)1-methyl-4-[3-(2-tolyl)-4-chloro-5-(1-fluoropropyl)]phenylpiperazine,

(14)1-(2-hydroxyethyl)-4-[3-(2-tolyl)-4-chloro-5-(1-fluoropropyl)]phenylpiperazine,

(15) 1-ethyl-4-[3-(2-tolyl)-4-chloro-5-(1-fluoropropyl]phenylpiperazine,

(16)1-methyl-4-[3-(2-tolyl)-4-chloro-5-ethanesulfonylamino]phenylpiperazine,

(17)1-methyl-4-[3-(2-tolyl)-4-chloro-5-propanesulfonylamino]phenylpiperazine,

(18)1-methyl-4-[3-(2-tolyl)-4-chloro-5-butanesulfonylamino]phenylpiperazine,

(19)1-ethyl-4-[3-(2-chlorophenyl)-4-chloro-5-ethanesulfonylamino]phenylpiperazine,

(20)1-ethyl-4-[3-(2-chlorophenyl)-4-chloro-5-propanesulfonylamino]phenylpiperazine,

(21)1-ethyl-4-[3-(2-chlorophenyl)-4-chloro-5-butanesulfonylamino]phenylpiperazine,

(22)1-methyl-4-[3-(2-chlorophenyl)-4-chloro-5-ethanesulfonylamino]phenylpiperazine,

(23)1-methyl-4-[3-(2-chlorophenyl)-4-chloro-5-propanesulfonylamino]phenylpiperazine,

(24)1-methyl-4-[3-(2-chlorophenyl)-4-chloro-5-butanesulfonylamino]phenylpiperazine,

(25)1-ethyl-4-[3-(4-fluorophenyl)-4-methoxy-5-ethanesulfonylamino]phenylpiperazine,

(26) 1-ethyl-4-(3-phenyl-4-methoxy-5-chloromethyl)phenylpiperazine,

(27)1-ethyl-4-{3-phenyl-4-methoxy-5-[1-fluoro-(4-pentenyl)]}phenylpiperazine,

(28) 1-ethyl-4-[3-phenyl-4-methoxy-5-(1-fluorobutyl)]phenylpiperazine,

(29) 1-ethyl-4-[3-phenyl-4-methoxy-5-(1-fluoropentyl)]phenylpiperazine,

(30) 1-ethyl-4-[3-(2-tolyl)-4-chloro-5-(1-fluorobutyl)]phenylpiperazine,

(31) 1-ethyl-4-[3-(2-tolyl)-4-fluoro-5-(1-fluorobutyl)]phenylpiperazine,

(32)1-ethyl-4-[3-(2-tolyl)-4-chloro-5-(1-fluoro-3-methylbutyl)]phenylpiperazine,

(33) 1-ethyl-4-[3-(2-tolyl)-4-chloro-5-(1-fluoroethyl)]phenylpiperazine,

(34)1-methyl-4-[3-(2-tolyl)-4-chloro-5-(1-fluorobutyl)]phenylpiperazine,

(35)1-ethyl-4-[3-(2-chlorophenyl)-4-chloro-5-(1-fluorobutyl)]phenylpiperazine,

(36)1-ethyl-4-[3-(2-tolyl)-4-chloro-5-(1,1-difluoropropyl)]phenylpiperazine,

(37) 1-ethyl-4-(3,5-diphenyl-4-methoxy)phenylpiperazine,

(38) 1-ethyl-4-(3-phenyl-4-methoxy)phenylpiperazine,

(39) 1-ethyl-4-(3,5-diphenyl-4-hydroxy)phenylpiperazine,

(40) 1-ethyl-4-(3-phenyl-4-methoxy-5-propyl)phenylpiperazine,

(41) 1-ethyl-4-(3,5-diphenyl-4-isopropoxy)phenylpiperazine,

(42) 1-ethyl-4-(3-phenyl-4-isopropoxy)phenylpiperazine,

(43) 1-ethyl-4-(3-phenyl-4-hydroxy)phenylpiperazine,

(44) 1-ethyl-4-[2-methoxy-3-phenyl-5-(3-hydroxypropyl)]phenylpiperazine,

(45) 1-hydroxyethyl-4-(3,5-diphenyl-4-methoxy)phenypiperazine,

(46) 1-ethyl-4-[3-(4-fluorophenyl)-4-methoxy-5-propyl)]phenylpiperazine,

(47) 1-ethyl-4-[3-phenyl-4-methoxy-5-(2-hydroxyethyl)]phenylpiperazine,

(48) 1-ethyl-4-[2-methoxy-3-phenyl-5-(2-hydroxyethyl)]phenylpiperazine,

(49) 1-ethyl-4-[3-phenyl-4-methoxy-5-(3-methoxypropyl)]phenylpiperazine,

(50)1-ethyl-4-[3-phenyl-4-methoxy-5-(3-methoxymethoxypropyl)]phenylpiperazine,

(51) 1-ethyl-4-(3-phenyl-4-methoxy-5-ethyl)phenylpiperazine,

(52) 1-ethyl-4-[3-phenyl-4-methoxy-5-(3-cyanopropyl)]phenylpiperazine,

(53)1-(2-fluoroethyl)-4-[3-(4-fluorophenyl)-4-methoxy-5-propyl]phenylpiperazine,

(54) 1-ethyl-4-[3-(4-methoxyphenyl)-4-methoxy-5-propyl]phenylpiperazine,

(55) 1-ethyl-4-(3-phenyl-4-methoxy-5-methoxycarbonyl)phenylpiperazine,

(56) 1-ethyl-4-[3-phenyl-4-methoxy-5-(2-hydroxypropyl)]phenylpiperazine,

(57) 1-ethyl-4-[3-phenyl-4-methoxy-5-(2-fluoroethyl)]phenylpiperazine,

(58) 1-ethyl-4-[3-phenyl-4-methoxy-5-(3-fluoropropyl)]phenylpiperazine,

(59)1-ethyl-4-[3-(4-fluorophenyl)-4-methoxy-5-isopropyl]phenylpiperazine,

(60)1-ethyl-4-[3-(4-fluorophenyl)-4-methoxy-6-isopropyl]phenylpiperazine,

(61)1-ethyl-4-[3-phenyl-4-methoxy-5-(1-hydroxyisopropyl)]phenylpiperazine,

(62) 1-ethyl-4-[3-phenyl-4-methoxy-5-(1-butoxypropyl)]phenylpiperazine,

(63) 1-ethyl-4-(3-phenyl-4-methoxy-5-propionyl)-phenylpiperazine,

(64) 1-ethyl-4-[3-phenyl-4-methoxy-5-(1-hydroxypropyl)]phenylpiperazine,

(65) 1-ethyl-4-[3-(2-fluorophenyl)-4-methoxy-5-propyl]phenylpiperazine,

(66)1-ethyl-4-[3-(4-trifluoromethylphenyl)-4-methoxy-5-propyl]phenylpiperazine,

(67)1-ethyl-4-[3-phenyl-4-methoxy-5-(1-fluoroisopropyl)]phenylpiperazine,

(68)1-ethyl-4-[3-phenyl-4-methoxy-5-(2-hydroxyisopropyl)]phenylpiperazine,

(69) 1-ethyl-4-[3-phenyl-4-methoxy-5-(1-fluoropropyl)]phenylpiperazine,

(70) 1-ethyl-4-(3-phenyl-4-methoxy-5-cyano)phenylpiperazine,

(71) 1-ethyl-4-[3-phenyl-4-methoxy-5-(2-furanyl)]-phenylpiperazine,

(72)1-ethyl-4-[3-(2,4-difluorophenyl)-4-methoxy-5-propyl]phenylpiperazine,

(73) 1-ethyl-4-(3-phenyl-4-methoxy-5-phenylacetyl)phenylpiperazine,

(74)1-ethyl-4-[3-phenyl-4-methoxy-5-(4-fluorophenyl)acetyl]phenylpiperazine,

(75)1-ethyl-4-[3-phenyl-4-methoxy-5-(1-hydroxyphenethyl)]phenylpiperazine,

(76)1-ethyl-4-[3-phenyl-4-methoxy-5-(2-tetrahydrofuranyl)]phenylpiperazine,

(77)1-ethyl-4-[3-phenyl-4-methoxy-5-(1-fluorophenethyl)]phenylpiperazine,

(78) 1-ethyl-4-[3-phenyl-4-methoxy-5-(2-pyridyl)]phenylpiperazine,

(79)1-ethyl-4-{3-phenyl-4-methoxy-5-[4-fluoro-(1-hydroxyimino)phenethyl]}phenylpiperazine,

(80)1-ethyl-4-{3-phenyl-4-methoxy-5-[1-fluoro-2-(2-pyridyl)ethyl]}phenylpiperazine,

(81) 1-ethyl-4-[3-phenyl-4-methoxy-5-(1-propenyl)]phenylpiperazine,

(82) 1-ethyl-4-[3-(3-fluorophenyl)-4-methoxy-5-propyl]phenylpiperazine,

(83) 1-ethyl-4-(3-phenyl-4-methoxy-5-hydroxymethyl)phenylpiperazine,

(84) 1-ethyl-4-[3-phenyl-4-methoxy-5-(4-pyridyl)acetyl]phenylpiperazine,

(85) 1-ethyl-4-(3-phenyl-4-methoxy-5-methanesulfinyl)phenylpiperazine,

(86) 1-ethyl-4-(3-phenyl-4-methoxy-5-ethanesulfinyl)phenylpiperazine,

(87) 1-ethyl-4-(3-phenyl-4-methoxy-5-formyl)phenylpiperazine,

(88) 1-ethyl-4-[3-phenyl-4-methoxy-5-(1,3-dioxan-2-yl)phenylpiperazine,

(89)1-ethyl-4-(3-phenyl-4-methoxy-5-cyclopropaneacetyl)phenylpiperazine,

(90)1-ethyl-4-[3-phenyl-4-methoxy-5-(2-pyridylcarbonyl)]phenylpiperazine,

(91) 1-ethyl-4-(3-phenyl-4-methoxy-5-amino)phenylpiperazine,

(92)1-ethyl-4-[3-phenyl-4-methoxy-5-(2-ethoxycarbonylethyl)]phenylpiperazine,

(93)1-ethyl-4-[3-phenyl-4-methoxy-5-(2-pyridyl)hydroxymethyl]phenylpiperazine,

(94) 1-ethyl-4-(3-phenyl-5-propyl-6-methoxy)phenylpiperazine,

(95) 1-ethyl-4-[3-phenyl-4-methoxy-5-(2-acetylethyl)]phenylpiperazine,

(96)1-ethyl-4-{3-phenyl-4-methoxy-5-[1-(2-pyridylmethoxy)propyl]}phenylpiperazine,

(97) 1-ethyl-4-[3-(2-tolyl)-4-methoxy-5-propyl]phenylpiperazine,

(98) 1-ethyl-4-(3-phenyl-4-methoxy-5-propylamino)phenylpiperazine,

(99) 1-(3-phenyl-4-hydroxy-5-phenylacetyl)phenylpiperazine,

(100) 1-ethyl-4-(3-phenyl-4-methoxy-5-benzylsulfinyl)phenylpiperazine,

(101)1-ethyl-4-(3-phenyl-4-methoxy-5-benzenesulfonylamino)phenylpiperazine,

(102)1-ethyl-4-{3-phenyl-4-methoxy-5-[1-fluoro-2-(4-pyridyl)ethyl]}phenylpiperazine,

(103)1-ethyl-4-[3-phenyl-4-methoxy-5-(N-ethanesulfonyl-N-methylamino)]phenylpiperazine,

(104)1-ethyl-4-(3-phenyl-4-methoxy-5-ethylaminosulfonyl)phenylpiperazine,

(105) 1-ethyl-4-(3-phenyl-4-methoxy-5-aminosulfonyl)phenylpiperazine,

(106) 1-(3-phenyl-4-methoxy-5-phenylacetyl)phenylpiperazine,

(107) 1-benzyl-4-(3-phenyl-4-methoxy-5-phenylacetyl)phenylpiperazine,

(108) 1-ethyl-4-[3-phenyl-4-chloro-5-(1-fluoropropyl)]phenylpiperazine,

(109)1-hydroxyethyl-4-(3-phenyl-4-methoxy-5-phenylacetyl)phenylpiperazine,

(110) 1-ethyl-4-[3-phenyl-5-(1-floropropyl)]phenylpiperazine,

(111) 1-ethyl-4-(3-phenyl-5-propionyl)phenylpiperazine,

(112)1-ethyl-4-[3-(2-tolyl)-4-chloro-5-(1-fluoropropyl)]phenylpiperazine,

(113)1-ethyl-4-[3-(2-methoxyphenyl)-4-methoxy-5-propyl]phenylpiperazine,

(114) 1-ethyl-4-(3-phenyl-4-methoxy-5-ethanesulfonyl)phenylpiperazine,

(115)1-ethyl-4-(3-phenyl-4-methoxy-5-dimethylaminosulfonyl)phenylpiperazine,

(116)1-ethyl-4-[3-phenyl-4-methoxy-5(1-pyrrolidinylsulfonyl)]phenylpiperazine,

(117)1-ethyl-4-[3-(2-tolyl)-4-chloro-5-(2,2,2-trifluoroethyl)sulfonylamino]phenylpiperazine,

(118)1-ethyl-4-[3-(2-tolyl)-4-chloro-5-(4-fluorophenylsulfonylamino)]phenylpiperazine,

(119) 1-ethyl-4-[3-phenyl-4-chloro-5-(1-hydroxypropyl)]phenylpiperazine,

(120) 1-ethyl-4-(3-phenyl-4-chloro-5-ethanesulfonyl)phenylpiperazine,

(121) 1-ethyl-4-(3-phenyl-4-chloro-5-propionyl)phenylpiperazine,

(122)1-ethyl-4-[3-(2-tolyl)-4-chloro-5-(1-pyrrolidylsulfonyl)]phenylpiperazine,

(123)1-ethyl-4-{3-[2-(4-fluorotolyl)]-4-chloro-5-(1-fluoropropyl)}phenylpiperazine,

(124)1-ethyl-4-[3-(2-methoxyphenyl)-4-chloro-5-(1-fluoropropyl)]phenylpiperazine,

(125)1-ethyl-4-[3-(2,4-difluorophenyl)-4-chloro-5-(1-fluoropropyl)]phenylpiperazine,

(126)1-ethyl-4-[3-(2-methoxymethylphenyl)-4-(chloro-5-(1-fluoropropyl)]phenylpiperazine,

(127)1-ethyl-4-{3-[2-(4-fluorotolyl)]-4-chloro-5-cyclopropaneaminosulfonyl}phenylpiperazine,

(128) 1-ethyl-4-[3-phenyl-4-chloro-5-(1-methylpropyl)]phenylpiperazine,

(129)1-ethyl-4-{3-[2-(4-fluorotolyl)]-4-chloro-5-cyclopropylmethylsulfonyl}phenylpiperazine,

(130) 1-ethyl-4-(3-phenyl-4-fluoro-5-ethanesulfonyl)phenylpiperazine,

(131)1-[3-(4-pyridyl)propyl]-4-[3-(2-tolyl)-4-chloro-5-(1-fluoropropyl)]phenylpiperazine,

(132)1-propyl-4-[3-(2-tolyl)-4-chloro-5-(1-fluoropropyl)]phenylpiperazine,

(133)1-ethyl-4-[3-(2-hydroxymethylphenyl)-4-chloro-5-(1-fluoropropyl)]phenylpiperazine,

(134)1-ethyl-4-[3-(2-tolyl)-4-chloro-5-propanesulfonylamino]phenylpiperazine,

(135)1-ethyl-4-[3-(2-tolyl)-4-chloro-5-dimethylaminosulfonyl]phenylpiperazine,

(136)1-ethyl-4-[3-(2-tolyl)-4-fluoro-5-methanesulfonyl]phenylpiperazine,

(137)1-ethyl-4-[3-(2-chloro-4-fluorophenyl)-4-chloro-5-(1-fluoropropyl)]phenylpiperazine,

(138)1-ethyl-4-[3-(2-tolyl)-4-chloro-5-(1-ethylpropyl)]phenylpiperazine,

(139)1-ethyl-4-[3-(2-tolyl)-4-chloro-5-methanesulfonyl]phenylpiperazine,

(140)1-ethyl-4-[3-(2-tolyl)-4-chloro-5-propanesulfonyl]phenylpiperazine,

(141)1-ethyl-4-[3-(2-tolyl)-4-chloro-5-(1-fluoro-4-pentenyl)]phenylpiperazine,

(142)1-ethyl-4-[3-(2-tolyl)-4-chloro-5-propylaminosulfonyl]phenylpiperazine,

(143)1-ethyl-4-[3-(2-tolyl)-4-chloro-5-ethanesulfonylamino]phenylpiperazine,

(144)1-ethyl-4-[3-(2-chlorophenyl)-4-chloro-5-(2,2,2-trifluoroethyl)sulfonylamino]phenylpiperazine,

(145)1-ethyl-4-[3-(2-tolyl)-4-cyano-5-(1-fluoropropyl)]phenylpiperazine,

(146)1-ethyl-4-[3-(2-tolyl)-4-chloro-5-(3-chloropropyl)sulfonylamino]phenylpiperazine,

(147)1-ethyl-4-[3-(2-tolyl)-4-chloro-5-phenylaminosulfonyl]phenylpiperazine,

(148)1-ethyl-4-[3-(2-tolyl)-4-chloro-5-benzyloxymethyl]phenylpiperazine,

(149) 1-ethyl-4-[3-(2-tolyl)-4-chloro-5-propoxymethyl]phenylpiperazine,

(150)1-ethyl-4-[3-(2-tolyl)-4-chloro-5-(4-pyridyl)methoxymethyl]phenylpiperazine,

(151) 1-ethyl-4-(3-phenyl-4-methoxy-5-propanesulfonyl)phenylpiperazine,

(152) 1-ethyl-4-(3-phenyl-4-methoxy-5-butanesulfonyl)phenylpiperazine,

(153)1-ethyl-4-[3-phenyl-4-methoxy-5-(2-fluoroethane)sulfonyl]phenylpiperazine,

(154) 1-ethyl-4-[3-(2-tolyl)-4-chloro-5-ethoxymethyl]phenylpiperazine,

(155)1-methyl-4-[3-(2-tolyl)-4-chloro-5-(1-hydroxybutyl)]phenylpiperazine,

(156) 1-ethyl-4-[3-(2-tolyl)-4-chloro-5-allyloxymethyl]phenylpiperazine,

(157)1-ethyl-4-[3-(2-tolyl)-4-chloro-5-cyclopropylmethoxymethyl]phenylpiperazine,

(158)1-ethyl-4-[3-(2-tolyl)-4-chloro-5-(1-pyrrolidinyl)]phenylpiperazine,

(159)1-methyl-4-[3-(2-chlorophenyl)-4-chloro-5-(1-fluorobutyl)]phenylpiperazine,

(160)1-methyl-4-[3-(2-chlorophenyl)-4-chloro-5-benzylsulfonylamino]phonylpiperazine,

(161)1-methyl-4-[3-(2-chlorophenyl)-4-chloro-5-propanesulfonyl]phenylpiperazine,

(162)1-ethyl-4-{3-phenyl-4-methoxy-5-[3-(4-fluorophenoxy)propane]sulfonyl}phenylpiperazine,

(163)1-methyl-4-[3-(2-chlorophenyl)-4-chloro-5-isopropylsulfonylamino]phenylpiperazine,

(164)1-ethyl-4-[3-phenyl-4-methoxy-5-(2-cyanoethylsulfonyl)]phenylpiperazine,

(165)1-ethyl-4-(3-phenyl-4-chloro-5-propanesulfonyamino)phenylpiperazine,

(166) 1-ethyl-4-[3-(2-tolyl)-4-chloro-5-difluoromethyl]phenylpiperazine,

(167)1-ethyl-4-[3-phenyl-4-methoxy-5-(1,1-difluoropropyl)]phenylpiperazine,

(168)1-ethyl-4-[3-(4-methoxyphonyl)-4-chloro-5-propanesulfonylamino]phenylpiperazine,

(169)1-methyl-4-[3-(2-chlorophenyl)-4-chloro-5-methanesulfonylamino]phenylpiperazine,

(170)1-ethyl-4-[3-(2,4-dichlorophenyl)-4-chloro-5-propanesulfonylamino]phenylpiperazine,

(171) 1-ethyl-4-[3-(2-tolyl)-4-chloro-5-propanedithio]phenylpiperazine,

(172)1-ethyl-4-[3-phenyl-4-chloro-5-(1,3-dithian-2-yl)]phenylpiperazine,

(173)1-ethyl-4-[3-(2-tolyl)-4-chloro-5-propanesulfonylaminomethyl]phenylpiperazine,

(174)1-methyl-4-[3-(4-fluorophenyl)-4-methoxy-5-propanesulfonyl]phenylpiperazine,

(175)1-ethyl-4-[3-(2-ethylphenyl)-4-chloro-5-propanesulfonylamino]phenylpiperazine,

(176)1-hydroxyethyl-4-[3-(4-fluorophenyl)-4-methoxy-5-ethanesulfonyl]phenylpiperazine,

(177)1-ethyl-4-[3-(2-formylphenyl)-4-chloro-5-propanesulfonylamino]phenylpiperazine,

(178)1-ethyl-4-[3-(2-cyanophenyl)-4-chloro-5-propanesufonylamino]phenylpiperazine,

(179)1-(2-pyridylethyl)-4-[3-(4-fluorophenyl)-4-methoxy-5-ethanesulfonyl]phenylpiperazine,

(180)1-(2-pyridylmethyl)-4-[3-(4-fluorophenyl)-4-methoxy-5-ethanesulfonyl]phenylpiperazine,

(181)1-(3-pyridylmethyl)-4-[3-(4-fluorophenyl)-4-methoxy-5-ethanesulfonyl]phenylpiperazine,

(182)1-(4-pyridylethyl)-4-[3-(4-fluorophenyl)-4-methoxy-5-ethanesulfonyl]phenylpiperazine,

(183) 1-[3-(4-fluorophenyl)-4-methoxy-5-ethanesulfonyl]phenylpiperazine,

(184)1-(2-fluoroethyl)-4-[3-(4-fluorophenyl)-4-methoxy-5-ethanesulfonyl]phenylpiperazine,

(185)1-ethyl-4-[3-(2-chlorophenyl)-4-chloro-5-(1-propenyl)]phenylpiperazine,

(186)1-ethyl-4-[3-(2-chlorophenyl)-4-chloro-5-(1-chloropropyl)]phenylpiperazine,

(187) 1-methyl-4-[3-phenyl-4-chloro-5-(1-fluoropropyl)]phenylpiperazine,

(188)1-methyl-4-[3-(2-hydroxymethylphenyl)-4-chloro-5-(1-fluoropropyl)]phenylpiperazine,

(189)1-ethyl-4-[3-(2-fluoromethylphenyl)-4-chloro-5-(1-fluoropropyl)]phenylpiperazine,

(190)1-methyl-4-{3-(2-fluoromethylphenyl)-4-chloro-5-[1-fluoropropyl]}phenylpiperazine,

(191)1-ethyl-4-{3-[2-(4-fluorotolyl)]-4-chloro-5-[1-fluoropropyl]}phenylpiperazine,

(192)1-[2-(2-pyridyl)ethyl]-4-[3-(2-tolyl)-4-chloro-5-(1-fluoropropyl)]phenylpiperazine,

(193)1-[2-(2-pyridyl)ethyl]-4-[3-(2-cyanophenyl)-4-chloro-5-(1-fluoropropyl)]phenylpiperazine,

(194)1-ethyl-4-[3-(2,6-xylyl)-4-chloro-5-(1-fluoropropyl)]phenylpiperazine,

(195)1-ethyl-4-{3-(2-trifluoromethylphenyl)-4-chloro-5-[1-fluoropropyl]}phenylpiperazine,

(196)1-ethyl-4-[3-(2-ethylphenyl)-4-chloro-5-(1-fluoropropyl)]phenylpiperazine,

(197)1-(2-hydroxyethyl)-4-[3-(2-ethylphenyl)-4-chloro-5-(1-fluoropropyl)]phenylpiperazine,

(198)1-(2-hydroxyethyl)-4-{3-(2-trifluoromethylphenyl)-4-chloro-5-[1-fluoropropyl]}phenylpiperazine,

(199)1-methyl-4-{3-(2-tolyl)-4-chloro-5-[1-fluoropropyl]}phenylpiperazine,and

(200)1-(2-hydroxyethyl)-4-{3-[2-(4-fluorotolyl)]-4-chloro-5-[1-fluoropropyl]}phenylpiperazine.

The biphenyl derivative represented by the formula (I) or (II) accordingto the present invention can be prepared by the following processes,though the processes for the preparation of the derivative are notlimited to them.

(1) biphenyl derivatives represented by the formula (I) or (II) whereinR¹ is a halogenated lower alkyl group, R³ is a cyano group, R⁵ is ahydroxy lower alkyl group, and n is 0

A phenylpiperazine derivative (III) is protected to form a protectedphenylpiperazine derivative (IV) the derivative (IV) is reacted with analkylmagnesium halide to form a protected hydroxyalkylphenylpiperazinederivative (V); the derivative (V) is reacted with a halogenating agentsuch as hexafluoropropene diethylamine, diethylaminosulfur trifluoride(hereinafter abbreviated to “DAST”), thionyl chloride and sulfurylchloride to form a protected halogenated alkylphenylpiperazinederivative (VI); the derivative (VI) is reacted with2-(1,3,2-dioxaborinan-2-yl)benzaldehyde in the presence oftetrakis(triphenylphosphine)palladium (0) and cesium carbonate to form aprotected halogenated alkylbiphenylpiperazine derivative (VII); thederivative (VII) is reacted with hydroxyamine to form a protectedhalogenated alkyl oxime biphenylpiperazine derivative (VIII); thederivative (VIII) is reacted with acetic anhydride in the presence ofpyridine and 4-dimethylaminopyridine to form a protected halogenatedalkylcyanobiphenylpiperazine derivative (IX); the derivative (IX) istreated with an acid to form a halogenated alkylcyanobiphenylpiperazinederivative (X); and the derivative (X) is reacted with a halogenatedalkanol.

The protected hydroxyalkylphenylpiperazine derivative (V) and thecompounds subsequent thereto may each have an asymmetric carbon atom inits molecule, and the objective compound can be prepared as an opticallyactive substance either by optical resolution of the correspondingcompound or by asymmetric synthesis, if necessary. In the opticalresolution, optically active cis-2-benzamidocyclohexane carboxylic acid(hereinafter abbreviated to “cis acid”), optically active dibenzoyltartaric acid (hereinafter abbreviated to “DBTA”), di-p-toluoyl tartaricacid (hereinafter abbreviated to “DTTA”) and the like may be used as areagent for optical resolution.

This process is illustrated by the following reaction scheme:

wherein R², R⁴, R⁶, R⁷, R⁸ and R⁹ are each as defined above.

(2) biphenyl derivatives represented by the formula (I) or (II) whereinR¹ is a halogenated lower alkyl group; R³ is one of various groupsincluding cyano group; R⁵ is one of various groups including hydroxylower alkyl group; and n is 0

Such biphenyl derivatives can be prepared by one of the following threeprocesses:

(i) a nitrobenzoic acid ester derivative (XIV) is hydrolyzed and theresulting product is reacted with a chlorinating agent such as oxalylchloride to form a nitrobenzoyl chloride derivative (XV); thisderivative (XV) is reacted with an alkylmalonic acid ester in thepresence of a base to form a malonic acid ester derivative (XVI); thisderivative (XVI) is treated with an acid or a base to form anacylnitrobenzene derivative (XVII); this derivative (XVII) is reducedwith sodium borohydride, diisopinocanephenylboron B-chloride(Dip-chloride) or the like; the resulting product is reacted with ahalogenating agent to form a halogenated alkylnitrobenzene derivative(XVIII): this derivative (XVIII) is reduced into a halogenatedalkylaniline derivative (XIX); this derivative (XIX) is reacted withbis(2-chloroethyl)amine to form a halogenated alkylphenylpiperazinederivative (XX); this derivative (XX) is reacted with a2-(1,3,2-dioxaborinan-2-yl)benzene derivative or the like in thepresence of triphenylphosphinepalladium [Pd(PPh₃)₄] and tripotassiumphosphate to form a biphenylpiperazine derivative (XXI); and thisderivative (XXI) is reacted with a halogenated alkanol or the like.

The halogenated alkylnitrobenzene derivative (XVIII) and the compoundssubsequent thereto may each have an asymmetric carbon atom in itsmolecule, and the objective compound can be prepared as an opticallyactive substance either by optical resolution of the correspondingcompound or by asymmetric synthesis, if necessary.

(ii) a phenylpiperazine derivative (III) derived from a nitrobenzoicacid ester derivative (XIV) is protected to form a protectedpiperazylbenzoic acid derivative (XXII); this derivative (XXII) isreacted with 2-mercaptopyridine or the like to form an active ester;this ester is reacted with a Grignard reagent such as alkylmagnesiumbromide to form a protected acylphenylpiperazine derivative (XXIII);this derivative (XXIII) is reduced with sodium borohydride or the liketo form a protected hydroxyalkylphenylpiperazine derivative (V); thisderivative (V) is reacted with a halogenating agent to form a protectedhalogenated atkylphenylpiperazine derivative (VI); this derivative (VI)is deprotected to form a halogenated alkylphenylpiperazine derivative(XX); and this derivative (XX) is treated in a similar manner to that ofthe process (i).

The protected hydroxyalkylphenylpiperazine derivative (V) and thecompounds subsequent thereto may each have an asymmetric carbon atom inits molecule, and the objective compound can be prepared as an opticallyactive substance either by optical resolution of the correspondingcompound or by asymmetric synthesis, if necessary.

(iii) a dibromoaniline derivative (XXIV) is reacted withbis(2-chloroethyl)amine to form a dibromophenylpiperazine derivative(XXV); this derivative (XXV) is protected to form a protecteddibromophenylpiperazine derivative (XXVI); this derivative (XXVI) isconverted into a protected hydroxyalkylphenylpiperazine derivative (V)either by reacting the derivative (XXVI) with a base and an acidanhydride to form a protected acylphenylpiperazine derivative (XXIII)and converting the derivative (XXIII) into the derivative (V) or byreacting the derivative (XXVI) with a base and a lower aliphaticaldehyde; and this derivative (V) is treated in a similar manner to thatof the process (ii).

These processes (i) to (iii) can be illustrated by the followingreaction scheme:

wherein R², R³, R⁴, R⁷ and R⁹ are each as defined above; R¹² representsa lower alkyl group; L represents a leaving group; and Ph represents aphenyl group.

(3) biphenyl derivatives represented by the formula (I) or (II) whereinR¹ is a lower alkylsulfonylamino group, R³ and R⁴ are the same ordifferent from each other and each is a lower alkyl group or the likeand n is 0

A phenylpiperazine derivative (III) is reacted with an alkyl halide toform a phenylalkylpiperazine derivative (XI); the derivative (XI) isreacted with tolylboric acid in the presence of palladium acetate toform a biphenylalkylpiperazine derivative (XII); the derivative (XII) ishydrolyzed; the product of this hydrolysis is reacted with ethylchlorocarbonrate in the presence of triethylamirie; the resultingproduct is reacted with sodium azide and a base successively to form anaminobiphenylalkylpiperazine derivative (XIII); and the derivative(XIII) is reacted with an alkylsulfonyl halide.

This process is illustrated by the following reaction scheme:

wherein R², R³, R⁴, R⁶ and R⁹ are each as defined above.

The biphenyl derivatives of the present invention can be prepared from,e.g., known 2-phenyl-[1,3,2]-dioxaborinane derivatives and knownphenylboric acid derivatives of which specific examples will bedescribed below according to one of the production processes describedabove.

The following 2-phenyl-[1,3,2]-dioxaborinane derivatives and phenylboricacid derivatives can also be prepared according to known syntheticprocesses.

Specific Examples of 2-phenyl-[1,3,2]-dioxaborinane Derivatives (thosedescribed in the brackets are CAS registry numbers)

(1) 2-phenyl-[1,3,2]-dioxaborinane [4406-7-3],

(2) 2-(4-fluorophenyl)-[1,3,2]-dioxaborinane [156942-21-1],

(3) 2-(4-bromophenyl)-[1,3,2]-dioxaborinane [54947-91-0],

(4) 2-(4-methoxyphenyl)-[1,3,2]-dioxaborinane [155826-85-0],

(5) 2-(4-cyanophenyl)-[1,3,2]-dioxaborinane [152846-62-3],

(6) 2-(2-methoxyphenyl)-[1,3,2]-dioxaborinane [141522-26-1], and

(7) 2-(2,4-dichlorophenyl)-[1,3,2]-dioxaborinane [73852-21-8].

Specific Examples of Phenylboric Acid Derivatives (those described inthe brackets are CAS registry numbers)

(1) phenylboric acid [98-80-6],

(2) 2-fluorophenylboric acid [1993-03-9],

(3) 3-fluorophenylboric acid [768-35-4],

(4) 4-fluorophenylboric acid [1765-93-1],

(5) 2-chlorophenylboric acid [3900-89-8],

(6) 3-chlorophenylboric acid [63503-60-6],

(7) 4-chlorophenylboric acid [1679-18-1],

(8) 3-bromophenylboric acid [89598-96-9],

(9) 4-bromophenylboric acid [5467-74-3 or 130869-99-7],

(10) 4-iodophenylboric acid [5122-99-6],

(11) 2-cyanophenylboric acid [138642-62-3],

(12) 3-cyanophenylboric acid [150255-96-2],

(13) 4-cyanophenylboric acid [126747-14-6],

(14) 2-trifluoromethylphenylboric acid [1423-27-4],

(15) 3-trifluoromethylphenylboric acid [1423-26-3],

(16) 4-trifluoromethylphenylboric acid [128796-39-4],

(17) 2-ethylphenylboric acid [90002-36-1],

(18) 3-ethylphenylboric acid [90555-65-0],

(19) 4-ethylphenylboric acid [63139-21-9],

(20) 2-formylphenylboric acid [40138-16-7],

(21) 3-formylphenylboric acid [87199-16-4],

(22) 4-formylphenylboric acid [87199-17-5],

(23) 2-hydroxyphenylboric acid [87199-14-2],

(24) 3-hydroxyphenylboric acid [87199-15-3],

(25) 4-hydroxyphenylboric acid [59106-93-2],

(26) 2-methoxyphenylboric acid [5720-06-9],

(27) 3-methoxyphenylboric acid [10365-98-7],

(28) 4-methoxyphenylboric acid [5720-07-0],

(29) 2,4-dichlorophenylboric acid [68716-47-2],

(30) 2,3-difluorophenylboric acid [121219-16-7],

(31) 2,3,4-trimethoxyphenylboric acid [118062-05-8],

(32) 2-fluoro-3-trifluoromethylphenylboric acid [157834-21-4],

(33) 3,4-dichlorophenylboric acid [151169-75-4],

(34) 2,3-dichlorophenylboric acid [151169-74-3],

(35) 3-trifluoromethyl-4-methoxyphenylboric acid [149507-36-8],

(36) 3-fluoromethyl-4-methoxyphenylboric acid [149507-26-6],

(37) 3-chloro-4-fluorophenylboric acid [144432-85-9],

(38) 3-fluoro-4-chlorophenylboric acid [137504-86-0],

(39) 2,4-difluorophenylboric acid [144025-03-6],

(40) 2,4-di(trifluoromethyl)phenylboric acid [153254-09-2],

(41) 3-methoxy-4-chlorophenylboric acid [89694-47-3],

(42) 2,4-dimethoxyphenylboric acid [133730-34-4],

(43) 3,4-dimethoxyphenylboric acid [122775-35-3],

(44) 2,3-dimethoxyphenylboric acid [40972-86-9],

(45) 2-formyl-4-methoxyphenylboric acid [139962-95-1], and

(46) 3-formyl-4-methoxyphenylboric acid [121124-97-8].

Although the biphenyl derivative according to the present invention maybe present as a stereoisomer, the present invention is not limited inthis respect, but the derivative may be any of the stereoisomers thereofor a mixture of them. Further, the biphenyl derivative according to thepresent invention may be any of the geometrical isomers thereof or amixture of them.

The pharmacologically acceptable salt of the biphenyl derivativeaccording to the present invention includes inorganic acid additionsalts such as hydrochloride, sulfate, nitrate, hydrobromide,hydroiodide, perchlorate and phosphate; organic acid addition salts suchas oxalate, maleate, fumarate and succinate; sulfonic acid additionsalts such as methanesulfonate, ethanesulfonate, benzenesulfonate,p-toluenesulfonate and camphorsulfonate; and amino acid addition salts.

The present invention also relates to the phenypiperazine derivativerepresented by the above formula (XXVII) or salt thereof. The kind ofthe salt is not limited. The phenylpiperazine derivative represented bythe formula (XXVII) is novel and is useful as an intermediate for thepreparation of the biphenyl derivative represented by the formula (I) or(II) according to the present invention.

Specific examples of the phenylpiperazine derivative represented by theformula (XXVII) include the following compounds, though the derivative(XXVII) is not limited to them:

(1) 1-[3-bromo-4-chloro-5-(1-hydroxyethyl)]phenylpiperazine,

(2) 1-[3-bromo-4-chloro-5-(1-hydroxypropyl)]phenylpiperazine,

(3) 1-[3-bromo-4-chloro-5-(1-hydroxybutyl)]phenylpiperazine,

(4) 1-[3-bromo-4-chloro-5-(1-hydroxypentyl)]phenylpiperazine,

(5) 1-[3-bromo-4-chloro-5-(1-hydroxyhexyl)]phenylpiperazine,

(6)1-hydroxymethyl-4-[3-bromo-4-chloro-5-(1-fluoropropyl)]phenylpiperazine,

(7)1-hydroxyethyl-4-[3-bromo-4-chloro-5-(1-fluoropropyl)]phenylpiperazine,

(8)1-hydroxypropyl-4-[3-bromo-4-chloro-5-(1-fluoropropyl)]phenylpiperazine,

(9)1-hydroxybutyl-4-[3-bromo-4-chloro-5-(1-fluoropropyl)]phenylpiperazine,

(10)1-hydroxypentyl-4-[3-bromo-4-chloro-5-(1-fluoropropyl)]phenylpiperazine,

(11)1-hydroxyhexyl-4-[3-bromo-4-chloro-5-(1-fluoropropyl)]phenylpiperazine,

(12)1-hydroxyethyl-4-[3-bromo-4-chloro-5-(1-chloropropyl)]phenylpiperazine,

(13)1-hydroxyethyl-4-[3-bromo-4-chloro-5-(1-bromopropyl)]phenylpiperazine,

(14)1-hydroxyethyl-4-[3-bromo-4-chloro-5-(1-iodopropyl)]phenylpiperazine,

(15)1-(t-butoxy)carbonyl-4-[3-bromo-4-chloro-5-(1-fluoropropyl)]phenylpiperazine,

(16)1-ethoxycarbonyl-4-[3-bromo-4-chloro-5-(1-fluoropropyl)]phenylpiperazine,

(17)1-benzyloxycarbonyl-4-[3-bromo-4-chloro-5-(1-fluoropropyl)]phenylpiperazine,

(18) 1-formyl-4-[3-bromo-4-chloro-5-(1-fluoropropyl)]phenylpiperazine,

(19) 1-acetoxy-4-[3-bromo-4-chloro-5-(1-fluoropropyl)]phenylpiperazine,

(20) 1-benzyl-4-[3-bromo-4-chloro-5-(1-fluoropropyl)]phenylpiperazine,

(21)1-(2-trimethylsilyloxyethyl)-4-[3-bromo-4-chloro-5-(1-hydroxypropyl)]phenylpiperazine,

(22)1-(2-trimethylsilyloxyethyl)-4-[3-bromo-4-chloro-5-(1-fluoropropyl)]phenylpiperazine,

(23)1-(2-trimethylsilyloxyethyl)-4-[3-bromo-4-chloro-5-(1-chloroxypropyl)]phenylpiperazine,

(24)1-(2-trimethylsilyloxyethyl)-4-[3-bromo-4-chloro-5-(1-bromopropyl)]phenylpiperazine,

(25)1-(2-trimethylsilyloxyethyl)-4-[3-bromo-4-chloro-5-(1-iodopropyl)]phenylpiperazine,

(26) 1-(3,5-dibromo-4-chloro)phenylpiperazine,

(27) 1-(t-butoxycarbonyl)-4-(3,5-dibromo-4-methoxy)phenylpiperazine,

(28) 1-(t-butoxycarbonyl)-4-(3,5-dibromo-4-chloro)phenylpiperazine,

(29)1-methyl-4-[3-(2-tolyl)-4-chloro-5-ethanesulfonylamino]phenylpiperazine,

(30) 1-(3-bromo-4-chloro-5-ethoxycarbonyl)phenylpiperazine,

(31)1-(t-butoxycarbonyl)-4-(3-bromo-4-chloro-5-ethoxycarbonyl)phenylpiperazine,

(32) 1-ethyl-4-(3-bromo-4-chloro-5-ethoxycarbonyl)phenylpiperazine,

(33) 1-[3-bromo-4-chloro-5-(1-propenyl)]phenylpiperazine,

(34)1-(t-butoxycarbonyl)-4-(3-bromo-4-chloro-5-carboxy)phenylpiperazine,

(35)1-(t-butoxycarbonyl)-4-[3-bromo-4-chloro-5-(2-pyridylthio)carbonyl]phenylpiperazine,and

(36)1-(t-butoxycarbonyl)-4-(3-bromo-4-chloro-5-propionyl)phenylpiperazine.

The compound of the present invention exhibits an extremely high LD₅₀value and extremely high safeness.

The biphenyl derivative or the pharmacologically acceptable salt thereofaccording to the present invention may be used as an active ingredientof a therapeutic and ameliorative agent for a mental disorder. Examplesof the mental disorder include cerebrovascular disorder, aggressivebehavior due to senile dementia, mental excitation, poriomania,delirium, hallucination, hyperkinesia, schizophrenia, emotionaldisturbance, depression, neurosis, psychophysiologic disorder andanxiety neurosis. In other words, the diseases against which thebiphenyl derivative or the pharmacologically acceptable salt thereofaccording to the present invention may be clinically applicable arethose against which dopamine 2 receptor antagonism and/or serotonin 2receptor antagonism is efficacious.

The dosage form of the compound of the present invention includepreparations for oral administration such as powder, fine granule,granule, tablet, coated tablet and capsule; external preparations suchas ointment, plaster and suppository; and injection. That is, apharmacological composition of the present invention comprises atherapeutically or amelioratively effective amount of the biphenylderivative or the pharmacologically acceptable salt thereof describedabove and a pharmacologically acceptable vehicle.

These preparations can be each prepared by the use of a conventionalvehicle, filler or carrier according to a conventional method. Apreparation for oral administration according to the present inventionis prepared by adding a vehicle or filler and, if necessary, a binder,disintegrator, lubricant, color and/or corrigent to the biphenylderivative or the pharmaceutically acceptable salt thereof and shapingthe obtained mixture into a powder, fine granule, granule, tablet,coated tablet, capsule or the like.

Examples of the vehicle or filler include lactose, corn starch, sucrose,glucose, mannitol, sorbitol, crystalline cellulose and silicon dioxide;those of the binder include polyvinyl alcohol, polyvinyl ether,methylcellulose, ethylcellulose, acacia, tragacanth, gelatin, shellac,hydroxypropylmethylcellulose, hydroxypropylcellulose,polyvinylpyrrolidone, polypropylene glycol-polyoxyethylene blockcopolymer and meglumine; those of the disintegrator include starch,agar, gelatin powder, crystalline cellulose, calcium carbonate, sodiumhydrogen carbonate, calcium citrate, dextrin, pectin and calciumcarboxymethylcellulose; those of the lubricant include magnesiumstearate, talc, polyethylene glycol, silica and hardened vegetable oils;those of the color include those authorized as pharmaceutical additives;and those of the corrigent include cocoa powder, menthol, aromaticpowder, mentha oil, borneol and powdered cinnamon barks. Of course, thetablet and granule may be suitably coated with sugar or the like, ifnecessary.

An injection according to the present invention is prepared by adding apH modifier, solubilizing agent, isotonicity agent and, if necessary, anauxiliary solubilizer and/or stabilizer to the biphenyl derivative orthe pharmaceutically acceptable salt thereof, and formulating theobtained mixture in a conventional manner.

The method for preparing an external preparation according to thepresent invention is not limited, but may be any ordinary one. The basematerial to be used in this preparation includes various materialsconventionally used in the preparation of drugs, quasi drugs, cosmeticsand so on.

Specific examples of the base material to be used in the externalpreparation include animal and vegetable oils, mineral oils, ester oils,waxes, higher alcohols, fatty acids, silicone oils, surfactants,phospholipids, alcohols, polyhydric alcohols, water-soluble polymers,clay minerals and purified water, and examples of the material to beoptionally used at need include pH modifiers, antioxidants, chelatingagents, antiseptics, antifungal substances, coloring matters andfragrances, though the material is not limited to them. The externalpreparation may further contain a differentiation-inducing agent, ablood flow accelerator, a disinfectant, an antiphlogistic, a cellactivator, a vitamin, an amino acid, a humectant and/or a keratolytic.The above base materials are each used in such an amount as to give aconcentration ordinarily predetermined in the preparation of an externalpreparation.

The dose of the biphenyl derivative or the pharmacologically acceptablesalt thereof according to the present invention varies depending uponsymptom and degree thereof, age, complication and so on, and thereforecannot be limited. Further, the dose varies also depending upon the kindof the salt or route of administration. The dose per adult a day isgenerally 0.01 to 1000 mg, preferably 0.1 to 500 mg, still morepreferably 0.5 to 100 mg, which is administered orally, intravenously,as a suppository or transcutaneously.

The preparation processes of a 2-phenyl-[1,3,2]-dioxaborinane derivativeand a phenylboric acid derivative which are necessary for carrying outthe present invention will now be described specifically as PreparativeExamples. Other derivatives can also be prepared in manners similarthereto.

PREPARATIVE EXAMPLES Preparative Example 1

Synthesis of 2-cyanophenylboric Acid

12.4 ml of a 1.6 M solution of t-butyllithium in n-pentane was dropwiseadded to 23 ml of THF at −76° C. in about 10 minutes. Then, a solutionof 2.0 g (11.0 mmo ) of 2-bromobenzonitrile in 3.0 ml. of THF wasdropwise added to the resulting mixture at −76° C. in about 20 minutes,followed by the dropwise addition of 2.3 ml (19.8 mmol) oftrimethoxyborane in 7 minutes. The obtained mixture was stirred at −76°C. for 20 minutes, followed by the addition of 13.8 ml of 2Nhydrochloric acid. The obtained mixture was stirred at room temperaturefor 30 minutes and extracted with ethyl acetate. The ethyl acetate phasewas washed with water and a saturated brine, dried and distilled toremove the solvent. 15 ml of methylene chloride and 15 ml of n-hexanewere added to the obtained residue. The obtained mixture was stirred atroom temperature for 30 minutes to give a precipitate. The precipitatewas recovered by filtration and dried to give 0.9 g of the titlecompound (yield: 55.7%).

m.p.; 237˜240° C.; ¹H-NMR(400 MHz, CDCl₃); δ(ppm) 7.5˜8.1(5H, m),8.77(1H, m). ¹H-NMR(400 MHz, CDCl₃+D₂O); δ(ppm) 7.56(1H, dd, J=6.2, 7.3Hz), 7.64(1H, dd, J=6.2, 7.3 Hz), 7.71(1H, d, J=7.3 Hz), 8.05(1H, dd,J=7.3 Hz). IR(cm⁻¹, nujol): 2200.

Preparative Example 2

Synthesis of 2-(1,3,2-dioxaborinan-2-yl)benzonitrile

543 mg (3.7 mmol) of 2-cyanophenylboric acid was added to a solution of280 mg (3.7 mmol) of 1,3-propanediol in 5.4 ml of methylene chloride.The obtained mixture was stirred at room temperature for 1.5 hours,followed by the removal of formed water. The obtained mixture wasdistilled to remove the solvent under reduced pressure to give 0.7 g ofthe title compound (yield: 100%).

m.p.; 45˜48° C.; ¹H-NMR(400 MHz, CDCl₃); δ(ppm) 2.11(2H, m), 4.23(4H, d,J=5.5 Hz), 7.48(1H, dd, J=7.6, 7.6 Hz), 7.54(1H, dd, J=7.6, 7.6 Hz),7.68(1H, d, J=7.6 Hz), 7.87(1H, dd, J=7.6 Hz). MS m/z: 188[MH]⁺.

Examples will now be given to illustrate the present inventionspecifically, though it is needless to say that the present invention isnot limited to only them.

EXAMPLES Example 1

Synthesis of ethyl 5-nitrosalicrylate

1.5 kg (8.2 mol) of 5-nitrosalicylic acid was dissolved in 2000 ml oftriethyl orthoformate. The obtained solution was refluxed under heatingfor 3 hours to remove formed ethanol by distillation. The reactionmixture was cooled and then concentrated under reduced pressure. Theobtained residue was crystallized from isopropyl ether to give 1.74 kgof the title compound as a colorless crystal.

m.p.; 85° C.; ¹H-NMR(400 MHz, CDCl₃); δ(ppm) 11.5(1H, s), 8.9(1H, d),8.3(1H, d-d), 7.1(1H, d), 4.5(2H, q), 1.5(3H, t).

Example 2

Synthesis of ethyl 3-bromo-5-nitrosaliclate

1.74 kg (8.2 mol) of ethyl 5-nitrosalicylate and 700 g of potassiumacetate were dissolved in 5000 ml of acetic acid. 1.312 kg of brominewas dropwise added to the obtained solution at room temperature in onehour. Thereafter, the resulting mixture was further stirred for one hourand then concentrated under reduced pressure. The obtained residue wasdissolved in ethyl acetate. The obtained solution was washed with water,dehydrated and concentrated under reduced pressure. The obtained residuewas crystallized from isopropyl ether to give 2.38 kg of the titlecompound as a colorless crystal.

m.p.; 108° C.; ¹H-NMR(400 MHz, CDCl₃); δ(ppm) 12.3(1H, s), 8.9(1H, d)8.6(1H, d), 4.5(2H, q), 1.5(3H, t).

Example 3

Synthesis of ethyl 2-chloro-3-bromo-5-nitrobenzoate

2.38 kg (8.2 mol) of ethyl 3-bromo-5-nitrosalicylate was dissolved in3000 ml of DMF, followed by the dropwise addition of 1.26 kg ofphosphorus oxychloride at room temperature. The obtained mixture washeated to 90° C. and then maintained at that temperature under heatingfor 10 hours. The obtained mixture was cooled and then concentratedunder reduced pressure. The obtained residue was dissolved in ethylacetate and the obtained solution was washed with water, dehydrated andconcentrated under reduced pressure to give 2.25 kg of the titlecompound as a colorless oil.

¹H-NMR(400 MHz, CDCl₃); δ(ppm) 8.6(1H, d) 8.5(1H, d), 4.5(2H, q),1.4(3H, t).

Example 4

Synthesis of ethyl 2-chloro-3-bromo-5-aminobenzoate

2.25 kg (7.3 mol) of ethyl 2-chloro-3-bromo-5-nitrobenzoate wasdissolved in a mixture comprising 4000 ml of concentrated hydrochloricacid and 4000 ml of ethanol. 1 kg of powdered iron was added to theobtained solution in portions so as to maintain the bulk temperature at80° C. The reaction mixture was cooled, followed by the addition of asaturated brine. The resulting mixture was extracted with ethyl acetate.The organic phase was dried and concentrated under reduced pressure togive 1.8 kg of the title compound as a colorless oil.

¹H-NMR(400 MHz, CDCl₃); δ(ppm) 7.1(1H, d), 6.9(1H, d), 4.4(2H, q),3.9(2H, s), 1.2(3H, t).

Example 5

Synthesis of 1-(3-bromo-4chloro-5-ethoxycarbonyl)phenypiperazinehydrochloride

1.8 kg (6.5 mol) of ethyl 2-chloro-3-bromo-5-aminobenzoate and 1.2 kg(6.7 mol) of bis(2-chloroethyl)amine hydrochloride were dissolved in5000 ml of o-dichlorobenzene. The obtained solution was refluxed underheating for 3 hours and thereafter cooled by allowing to stand,precipitating a crystal. This crystal was recovered by filtration anddried to give 2.4 kg of the title salt.

m.p.; 250° C. or above; ¹H-NMR(400 MHz, CDCl₃); δ(ppm) 7.2(1H, d),7.1(1H, d), 4.4(2H, q), 3.2(4H, m), 3.0(4H, m), 1.4(3H, t).

Example 6

Synthesis of1-(t-butoxycarbonyl)4-(3-bromo-4-chloro-5-ethoxycarbonyl)phenylpiperazine

880 g (2.3 mol) of 1-(3-bromo-4-chloro-5-ethoxycarbonyl)phenypiperazinehydrochloride was suspended in a mixture comprising 500 g (5 mol) oftriethylamine and 2000 ml of acetonitrile, followed by the dropwiseaddition of 500 g of di-t-butyl carbonate under cooling with ice. Afterthe completion of the dropwise addition, the resulting mixture wasfurther stirred at room temperature for one hour and then concentrated.The obtained residue was dissolved in ethyl acetate and the obtainedsolution was washed with water, dried and concentrated under reducedpressure. The obtained residue was crystallized from isopropyl ether togive 1 kg of the title compound as a colorless crystal.

m.p.; 115° C.; ¹H-NMR(400 MHz, CDCl₃); δ(ppm) 7.2(1H, d), 7.1(1H, d),4.4(2H, q), 3.6(4H, t), 3.2(4H, t), 1.5(9H, s), 1.4(3H, t).

Example 7

Synthesis of1-(t-butoxycarbonyl)-4-[3-bromo-4-chloro-5-(1-hydroxypropyl)]phenylpiperazine

1 kg (2.23 mol) of1-(t-butoxycarbonyl)-4-(3-bromo-4-chloro-5-ethoxycarbonyl)phenylpiperazinewas dissolved in 4000 ml of THF, followed by the dropwise addition of5.5 mol of ethylmagnesium bromide under cooling with ice. The obtainedmixture was further stirred at room temperature for one hour, followedby the addition of a saturated aqueous solution of ammonium chloride.The obtained mixture was extracted with ethyl acetate. The organic phasewas washed with water, dried and concentrated under reduced pressure togive 1 kg of the title compound as a colorless oil. ¹H-NMR(400 MHz,CDCl₃); δ(ppm) 7.1(1H, d), 7.05(1H, d), 5.0(1H, m), 3.6(4H, t), 3.1(4H,t), 1.6(2H, m), 1.5(9H, s), 1.0(3H, t).

Example 8

Synthesis of1-(t-butoxycarbonyl)-4-[3-bromo-4-chloro-5-(1-fluoropropyl)]phenylpiperazine

1 kg (2.3 mol) of1-(t-butoxycarbonyl)-4-[3-bromo-4-chloro-5-(1-hydroxypropyl)]phenylpiperazinewas dissolved in 2000 ml of anhydrous methylene chloride, followed bythe dropwise addition of 425 g (2.6 mol) of diethylaminosulfurtrifluoride (DAST) at −70° C. After the completion of the dropwiseaddition, the obtained mixture was further stirred for 30 minutes andpoured into water. The aqueous phase was extracted with methylenechloride. The methylene chloride phase was washed with water, dried andconcentrated under reduced pressure. The obtained residue was purifiedby silica gel column chromatography (with ethyl acetate and hexane) togive 900 g of the title compound as a colorless oil.

¹H-NMR(400 MHz, CDCl₃); δ(ppm) 7.1(1H, d), 7.0(1H, d), 5.7(1H, m),3.6(4H, m), 3.2(4H, m), 1.8(2H, m), 1.5(9H, m), 1.0(3H, t).

Example 9

Synthesis of1-(t-butoxycarbonyl)-4-[3-(2-formylphenyl)-4-chloro-5-(1-fluoropropyl)]phenylpiperazine

174 g (0.4 mol) of1-(t-butoxycarbonyl)-4-[3-bromo-4-chloro-5-(1-fluoropropyl)]phenylpiperazine,114 g (0.6 mol) of 2-(1,3,2-dioxaborinan-2-yl)benzaldehyde (10)described in Synlett, (3), 207-210, 1992, 1 g oftetrakis(triphenylphosphine)palladium (0) and 195 g (0.6 mol) of cesiumcarbonate were dissolved in 1000 ml of DMF and the obtained solution wasmaintained at 100° C. for 3 hours to conduct a reaction. The reactionmixture was cooled and then poured into water. The resulting mixture wasextracted with ethyl acetate. The organic phase was washed with water,dried and concentrated under reduced pressure. The obtained residue waspurified by silica gel column chromatography and recrystallized from anethyl acetate/hexane mixture to give 165 g of the title compound as acolorless crystal.

m.p.; 135° C.; ¹H-NMR(400 MHz, CDCl₃); δ(ppm) 9.8(1H, d), 8.0(1H, m),7.7(1H, m), 7.5(1H, m), 7.3(1H, m), 7.1(1H, d), 6.8(1H, d), 5.8(1H, m),3.6(4H, m), 3.2(4H, m), 1.9(2H, m), 1.5(9H, s), 1.1(3H, t).

Example 10

Sythesis of1-(t-butoxycarbonyl)-4-[3-(2-hydroxyiminomethylphenyl)-4-chloro-5-(1-fluoropropyl)]phenylpiperazine

165 g (0.36 mol) of1-(t-butoxycarbonyl)-4-(3-(2-formylphenyl)-4-chloro-5-(1-fluoropropyl)]phenylpiperazineand 50 g (0.72 mol) of hydroxylamine hydrochloride were dissolved in 100ml of a 5N aqueous solution of NaOH, followed by the addition of 200 mlof ethanol. The obtained mixture was refluxed under heating for 2 hoursand thereafter cooled and concentrated under reduced pressure. Theresidue was partitioned between water and ethyl acetate. The organicphase was washed with water, dried and concentrated under reducedpressure to give 154 g of the title compound as a colorless oil.

¹H-NMR(400 MHz, CDCl₃); δ(ppm) 8.0(1H, m), 7.8(1H, d), 7.6(1H, m),7.4(1H, m), 7.2(1H, m), 7.1(1H, m), 6.7(1H, m), 5.8(1H, m), 3.6(4H, m),3.2(4H, m), 1.9(2H, m), 1.5(9H, s), 1.1(3H, t).

Example 11

Synthesis of1-(t-butoxycarbonyl)-4-[3-(2-cyanophenyl)-4-chloro-5-(1-fluoropropyl)]phenylpiperazine

154 g (0.32 mol) of1-(t-butoxycarbonyl)-4-[3-(2-hydroxyiminomethylphenyl)-4-chloro-5-(1-fluoropropyl)lphenylpiperazineand 40 g of N,N-dimethylaminopyridine were dissolved in a mixturecomprising 100 ml of acetic anhydride and 100 ml of pyridine. Theobtained solution was heated to 100° C. and maintained at thattemperature for one hour to conduct a reaction. The reaction mixture wascooled and then poured into a saturated aqueous solution of sodiumhydrogen carbonate. The resulting mixture was extracted with ethylacetate to give 140 g of the title compound as a colorless crystal.

m.p.; 120° C.; ¹H-NMR(400 MHz, CDCl₃); δ(ppm) 7.8(1H, d), 7.6(1H, t),7.5(1H, t), 7.4(1H, d), 7.1(1H, d), 6.8(1H, d), 5.9(1H, m), 3.6(4H, m),3.2(4H, m), 2.0(2H, m), 1.5(9H, s), 1.1(3H, t).

Example 12

Synthesis of1-[3-(2-cyanophenyl)-4-chloro-5-(1-fluoropropyl)phenylpiperazine

140 g (0.3 mol) of1-(t-butoxycarbonyl)-4-[3-(2-cyanophenyl)-4-chloro-5-(1-fluoropropyl)]phenylpiperazinewas dissolved in a mixture comprising 500 ml of trifluoroaceticanhydride and 500 ml of chloroform. The obtained solution was stirred at0° C. for 5 hours and distilled to remove the solvent. The residue wasrecrystallized from ethyl acetate and hexane to give 100 g of the titlecompound as a colorless crystal.

m.p.; 159° C.; ¹H-NMR(400 MHz, CDCl₃); δ(ppm) 7.8(1H, d), 7.6(1H, t),7.5(1H, t), 7.4(1H, d), 7.1(1H, d), 6.8(1H, d), 5.9(1H, m), 3.5(1H,b-s), 3.2(4H, m), 3.0(4H, m), 1.9(2H, m), 1.1(3H, t).

Example 13

Synthesis of1-(2-hydroxyethyl)-4-[3-(2-cyanophenyl)-4-chloro-5-(fluoropropyl)]phenylpiperazine

32.1 g (0.09 mol) of1-[3-(2-cyanophenyl)-4-chloro-5-(1-fluoropropyl)]phenylpiperazine, 12.5g of 2-bromoethanol and 20 g of triethylamine were dissolved in 100 mlof DMF. The obtained solution was heated to 50° C. and maintained atthat temperature for 24 hours to conduct a reaction. The reactionmixture was cooled and then partitioned between ethyl acetate and water.The ethyl acetate phase was washed with water, dried and concentratedunder reduced pressure. The residue was purified by silica gel columnchromatography (with methylene chloride/methanol) to give 22 g of thetitle compound as a colorless oil. This oily product was separated withan optically active column to recover a fraction having a plus angle ofrotation. Thus, 10 g of the optically active title compound was obtainedas a colorless oil. This product was treated with hydrochloric acid toform a salt thereof. The product was recrystallized from methanol/etherto give a hydrochloride of the title compound as a colorless crystal.

m.p. (hydrochloride); 244-245° C.; [a]_(D)=+6.3° (c=1.03, MeOH)(hydrochloride) ¹H-NMR (400 MHz, CDCl₃); δ(ppm) 7.8(1H, d), 7.6(1H, t),7.5(1H, t), 7.4(1H, d), 7.1(1H, d), 6.8(1H, d), 5.8(1H, m), 3.7(2H, t),3.3(4H, m), 2.7(4H, m), 2.6(2H, t), 1.9(2H, m), 1.1(3H, t).

Example 14

Synthesis of1-ethyl-4-(3-bromo-4-chloro-5-ethoxycarbonyl)phenylpiperazine

347 g (1 mol) of 1-(3-bromo-4-chloro-5-ethoxycarbonyl)phenypiperazinehydrochloride was dissolved in 1000 ml of DMF, followed by the additionof 207 g (1.5 mol) of potassium carbonate and 120 g (1.1 mol) of ethylbromide. The obtained mixture was stirred at room temperature overnight,followed by the addition of water. The resulting mixture was extractedwith ethyl acetate. The ethyl acetate phase was washed with water, driedand concentrated under reduced pressure to give 338 g of the titlecompound as a colorless oil.

¹H-NMR(400 MHz, CDCl₃); δ(ppm) 7.2(1H, d), 7.1(1H, d), 4.4(2H, q),3.2(4H, m), 2.6(4H, m), 2.5(2H, q), 1.4(3H, t), 1.1(3H, t).

Example 15

Synthesis of1-ethyl-4-[3-(2-tolyl)-4-chloro-5-ethoxylcarbonyl]phenylpiperazine

338 g (0.9 mol) of1-ethyl-4-(3-bromo-4-chloro-5-ethoxycarbonyl)phenylpiperazine and 136 g(1 mol) of 2-tolylboric acid [CH₃C₆H₄B(OH)₃] were dissolved in 3000 mlof DMF, followed by the addition of 20 g of palladium acetate, 55 g oftriphenylphosphine and 35 g of triethylamine. The obtained mixture wasstirred at 100° C. overnight, cooled and partitioned between ethylacetate and water. The ethyl acetate phase was washed with water, driedand concentrated under reduced pressure. The obtained residue waspurified by silica gel column chromatography (with methylenechloride/ethanol) to give 221 g of the title compound as a colorlessoil.

¹H-NMR(400 MHz, CDCl₃); δ(ppm) 8.0(1H, s), 7.3-7.1(4H, m), 6.8(1H, d),4.4(2H, q), 3.2(1H, m), 2.6(4H, m), 2.5(2H, q), 1.4(3H, t), 1.2(3H, t),1.1(3H, t).

Example 16

Synthesis of 1-ethyl-4-[3-(2-tolyl)-4-chloro-5-amino]phenylpiperazine

193 g (0.5 mol) of1-ethyl-4-[3-(2-tolyl)-4-chloro-5-ethoxylcarbonyl]phenylpiperazine wasdissolved in a mixture comprising 100 ml of 5N NaOH and 500 ml ofmethanol. The obtained solution was stirred at room temperature for 3hours and concentrated under reduced pressure. The obtained residue wasdissolved in 300 ml of DMF, followed by the addition of 61 g (0.6 mol)of triethylamine. 65 g. (0.6 mol) of ethyl chlorocarbonate was dropwiseadded to the obtained mixture under cooling with ice. The mixture thusobtained was stirred at 0° C. for 30 minutes, followed by the additionof 39 g (0.6 mol) of sodium azide. The resulting mixture was subjectedto reaction for 2 hours and then poured into water to precipitate awhite crystal. This white crystal was recovered by filtration andimmediately dissolved in 500 ml of toluene. The obtained solution washeated for one hour, followed by the addition of 300 ml of concentratedhydrochloric acid. The obtained mixture was maintained at 100° C. byheating for one hour, cooled, basified with 8N NaOH and extracted withethyl acetate. The ethyl acetate phase was washed with water, dried andconcentrated under reduced pressure. The obtained residue was purifiedby silica gel column chromatography to give 83 g of the title compoundas a colorless oil.

¹H-NMR(400 MHz, CDCl₃); δ(ppm) 7.3-7.1(4H, m), 6.3(1H, m), 6.2(1H, m),4.0(2H, s), 3.2(4H, m), 2.6(4H, m), 2.4(2H, q), 2.2(3H, m), 1.1(3H, m).

Example 17

Synthesis of1-ethyl-4-[3-(2-tolyl)-4-chloro-5-propanesulfonylamino]phenylpiperazinehydrochloride

3.3 g (10 mmol) of1-ethyl-4-[3-(2-tolyl)-4-chloro-5-amino]phenylpiperazine was dissolvedin 5 ml of pyridine, followed by the addition of 2.9 g (20 mmol) ofpropanesulfonyl chloride. The obtained mixture was stirred at roomtemperature overnight and partitioned between water and ethyl acetate.The ethyl acetate phase was washed with water, dried and concentratedunder reduced pressure. The obtained residue was purified by silica gelcolumn chromatography (with methylene chloride/ethanol) to give 2.6 g ofthe title compound as a colorless oil. This oil was treated withhydrochloric acid to form a hydrochloride thereof, and the product wasrecrystallized from methanol/ether to give the title compound as a whitecrystal.

m.p.; 135° C.; ¹H-NMR(400 MHz, CDCl₃); δ(ppm) 7.3(4H, m), 7.0(1H, d),6.8(1H, m), 4.8(1H, t), 4.4(2H, d), 3.2(4H, m), 2.9(2H, m), 2.6(4H, m),2.5(2H, q), 2.1(3H, s), 1.8(2H, m), 1.1(3H, t), 1.0(3H, t).

The following compounds were prepared in a similar manner to that of theExample 17 except that the propanesulfonyl chloride was replaced byethanesulfonyl chloride or butanesulfonyl chloride.

Example 18

1-Ethyl-4-[3-(2-tolyl)-4-chloro-5-ethanesulfonylamino]phenylpiperazine

m.p.; 155° C.; ¹H-NMR(400 MHz, CDCl₃); δ(ppm) 7.7-7.2(4H, m), 7.0(1H,d), 6.6(1H, m), 3.7(2H, q), 3.3(4H, m), 2.4(2H, q), 2.1(3H, s), 1.4(3H,t), 1.2(3H, t), 1.1(3H, t).

Example 19

1-Ethyl-4-[3-(2-tolyl)-4-chloro-5-butanesulfonylamino]phenylpiperazine

m.p.; 175° C.; ¹H-NMR(400 MHz, CDCl₃); δ(ppm) 7.7-7. 2(4H, m), 7.1(1H,d), 6.6(1H, d), 3.2(4H, m), 3.1(2H, m), 2.6(4H, m), 2.5(2H, q), 2.1(3H,s), 1.8(2H, m), 1.4(2H, m), 1.1(3H, t), 0.9(3H, t).

The following compounds were prepared as colorless oils in yields of 85and 90% respectively in a similar manner to that of the Example 13except that the 2-bromoethamol was replaced by methyl iodide or ethyliodide.

Example 20

1-Methyl-4-[3-(2-cyanophenyl)-4-chloro-5-(1-fluoropropyl)]phenylpiperazine

¹H-NMR(400 MHz, CDCl₃); δ(ppm) 7.8(1H, d), 7.65(1H, t), 7.5(1H, t),7.4(1H, d), 7.1(1H, d), 6.8(1H, d), 5.8(1H, m), 3.2(4H, m), 2.6(4H, m),2.4(3H, s), 2.0(2H, m), 1.1(3H, t).

Example 21

1-Ethyl-4-[3-(2-cyanophenyl)-4-chloro-5-(1-fluoropropyl)phenylpiperazine

¹H-NMR(400 MHz, CDCl₃); δ(ppm) 7.8(1H, d), 7.6(1H, t), 7.5(1H, t),7.0(1H, d), 7.1(1H, d), 6.8(1H, d), 5.8(1H, m), 3.3(4H, m), 2.6(4H, m),2.5(2H, q), 2.0(3H, m), 1.2(3H, t), 1.1(3H, t).

The following compounds were prepared by effecting the process describedin Example 9 except that the 2-(1,3,2)-dioxaborinan-2-yl)benzaldehydewas replaced by 2-chlorophenyl-1,3,2-dioxaborinane, and subsequentlyeffecting the process described in Examples 12 or 13.

Example 22

1-Methyl-4-[3-(2-chlorophenyl)-4-chloro-5-(1-fluoropropyl)]phenylpiperazine

¹H-NMR(400 MHz, CDCl₃); δ(ppm) 7.5(1H, m), 7.3(2H, m), 7.2(1H, m),7.1(1H, d), 6.8(1H, s), 5.8(1H, m), 3.2(4H, m), 2.3(3H, s), 2.0(3H, m),1.0(3H, t).

Example 23

1-(2-Hydroxyethyl)-4-[3-(2-chlorophenyl)-4-chloro-5-(1-fluoropropyl)]phenylpiperazine

¹H-NMR(400 MHz, CDCl₃); δ(ppm) 7.5(1H, m), 7.3(2H, m), 7.2(1H, m),7.05(1H, d), 6.8(1H, d), 5.8(1H, m), 3.2(4H, m), 2.6(4H, m), 2.5(2H, q),2.0(2H, m), 1.2(3H, t), 1.1(3H, d-t).

Example 24

1-Ethyl-4-[3-(2-chlorophonyl)-4-chloro-5-(1-fluoropropyl)]phenylpiperazine

¹H-NMR(400 MHz, CDCl₃); δ(ppm) 7.5-7.2(4H, m) 7.1(1H, d), 6.8(4H, m),5.8(1H, m), 3.7(4H, m), 3.2(4H, m), 2.7(4H, m), 2.6(2H, m), 2.0(2H, m),1.6(1H, b-s), 1.1(3H, d-t).

The following compounds were prepared in a similar manner to that of theExample 9 except that the 2-(1,3,2-dioxaborinan-2-yl)benzaldehyde wasreplaced by 2-tolyl-1,3,2-dioxaborinane.

Example 25

1-Methyl-4-[3-(2-tolyl)-4-chloro-5-(1-fluoropropyl)]phenylpiperazine

¹H-NMR(400 MHz, CDCl₃); δ(ppm) 7.3-7.2(3H, m), 7.1(1H, m), 7.0(1H, d),6.7(1H, d), 6.8(1H, m), 3.2(4H, m), 2.6(4H, m), 2.3(3H, s), 2.1(3H, d),1.9(2H, m), 1.1(3H, m).

Example 26

1-(2-Hydroxyethyl)-4-[3-(2-tolyl)-4-chloro-5-(1-fluloropropyl)]phenylpiperazine

¹H-NMR(400 MHz, CDCl₃); δ(ppm) 7.3-7.2(3H, m) 7.1(1H, m), 7.0(1H, d),6.7(1H, d), 5.8(1H, m), 3.7(2H, t), 3.2(4H, m), 2.7(2H, t), 2.6(2H, t),2.1(3H, d), 1.9(2H, m), 1.1(3H, m).

Example 27

1-Ethyl-4-[3-(2-tolyl )-4-chloro-5-(1-fluloropropyl)]phenylpiperazine

¹H-NMR(400 MHz, CDCl₃); δ(ppm) 7.3-7.2(3H, m) 7.1(1H, m), 7.0(1H, d),6.7(1H, d), 5.8(1H, m), 3.2(4H, m), 2.6(4H, m), 2.5(2H, q), 2.1(3H, d),1.9(2H, m), 1.15(3H, t), 1.05(3H, m).

The following compounds were prepared first in the same manner as thatof the Example 14 except that the ethyl bromide was replaced by methyliodide, then in the same manner as that of the Example 15 wherein the2-tolylboric acid was used or replaced by 2-chloroboronic acid.

Example 28

1-Methyl-4-[3-(2-tolyl)-4-chloro-5-ethanesulfonylamino]phenylpiperazine

¹H-NMR(400 MHz, CDCl₃); δ(ppm) 7.3(4H, m), 7.1(1H, d), 6.6(1H, d),3.3(4H, m), 3.2(2H, q), 2.6(4H, m), 2.4(3H, s), 2.1(3H, s), 1.4(3H, t).

Example 29

1-Methyl-4-[3-(2-tolyl)-4-chloro-5-propanesulfonylamino]phenylpiperazine

¹H-NMR (400 MHz, CDCl₃); δ(ppm) 7.5(1H, m), 7.4-7.2(4H, m), 6.5(1H, m),3.2(4H, m), 2.6(4H, m), 2.4(3H, s), 1.2(3H, m).

Example 30

1-Methyl-4-(2-tolyl)-4-chloro-5-butanesulfonylamino]phenylpiperazine

¹H-NMR(400 MHz, CDCl₃); δ(ppm) 7.3(4H, m), 7.1(1H, d), 6.6(1H, m),3.2(4H, m), 3.1(2H, m), 2.6(4H, m), 2.3(3H, s), 2.1(3H, s), 1.8(2H, m),1.4(2H, m), 0.9(3H, t).

Example 31

1-Ethyl-4-[3-(2-chlorophenyl)-4-chloro-5-ethanesulfonylamino]phenylpiperazine

¹H-NMR(400 MHz, CDCl₃); δ(ppm) 7.7(2H, m), 7.2-7.5)(4H, m), 6.6(1H, d),3.3(4H, m), 3.1(2H, q), 2.6(4H, m), 2.5(2H, q), 1.4(3H, t), 1.1(3H, t).

Exampel 32

1-Ethyl-4-[3-(2-chlorophenyl)-4-chloro-5-propanesulfonylamino]phenylpiperazine

¹H-NMR(400 MHz, CDCl₃); δ(ppm) 7.5(1H, m), 7.4(2H, m), 7.3(1H, m),7.0(1H, d), 6.8(1H, d), 3.8(2H, m), 3.6(4H, m), 3.2(2H, m), 3.1(4H, m),1.7(2H, q), 1.2(3H, t), 0.9(3H, t).

Example 33

1-Ethyl-4-[3-(2-chlorophenyl)-4-chloro-5-butanesulfonylamino]phenylpiperazine

¹H-NMR(400 MHz, CDCl₃); δ(ppm) 7.7-7.2(5H, m), 6.6(1H, m), 3.2(4H, m),3.1(2H, m), 2.6(4H, m), 2.5(2H, q), 1.8(2H, m), 1.4(2H, m), 1.1(3H, t),0.9(3H, t).

Example 34

1-Methyl-4-[3-(2-chlorophenyl)-4-chloro-5-ethanesulfonylamino]phenylpiperazine

¹H-NMR(400 MHz, CDCl₃); δ(ppm) 7.5(1H m), 7.4-7.2(4H, m), 6.8(1H, b-s),6.6(1H, d), 3.25(4H, m), 3.2(2H, q), 2.6(4H, m), 2.4(3H, s), 1.4(3H, t).

Example 35

1-Methyl-4-[3-(2-chloropheyl)-4-chloro-5-propanesulfonylamino]phenylpiperazine

¹H-NMR(400 MHz, CDCl₃); δ(ppm) 7.5(1H, m), 7.4-7.2(4H, m), 6.6(1H, d),3.2(4H, m), 3.1(2H, m), 2.6(4H, m), 2.4(3H, s), 1.2(3H, m), 1.0(3H, t).

Example 36

1Methyl-4-[3-(2-chlorophenyl)-4-chloro-5-butanesulfonylamino]phenylpiperazine

¹H-NMR(400 MHz, CDCl₃); δ(ppm) 7.5(1H, m), 7.4-7.2(4H, m), 6.6(1H, m),3.2(4H, m), 3.1(2H, m), 2.6(4H, m), 2.4(3H, s), 1.8(2H, m), 1.4(2H, m),0.9(3H, t).

Example 37

Synthesis of1-(t-butoxycarbonyl)-4-(3,5-dibromo-4-methoxy)phenylpiperazine

440 g of the title compound was prepared from 350 g of1-(3,5-dibromo-4-methoxy)phenylpiperazine in a similar manner to that ofthe Example 6.

¹H-NMR(400 MHz, CDCl₃); δ(ppm) 7.0(2H, m), 3.8(3H, s), 3.5(4H, m),3.0(4H, m), 1.2(9H, s).

Example 38

Synthesis of1-(t-butoxycarbonyl-4-(3-bromo-4-methoxy-5-ethanesulfonylamino]phenylpiperazine

440 g (0.97 mol) of1-(t-butoxycarbonyl)-4-(3,5-dibromo-4-methoxy)phenylpiperazine wasdissolved in 2000 ml of THF, followed by the dropwise addition of 1.2equivalents of n-butyllithium at −78° C. The obtained mixture was assuch stirred for 30 minutes. Sulfur dioxide gas was blown into theresulting mixture for one hour, followed by the addition of 1.2equivalents of ethyl iodide. The mixture was brought to a roomtemperature and then partitioned between water and ethyl acetate. Theorganic phase was washed with water, dried and concentrated underreduced pressure to give 250 g of the title compound.

¹H-NMR(400 MHz, CDCl₃); δ(ppm) 7.4(1H, m), 7.3(1H, m), 4.0(3H, s),3.6(4H, m), 3.4(2H, q), 3.2(4H, m), 1.5(9H, s), 1.2(3H, t).

Example 39

Synthesis of1-(t-butoxycarbonyl)-4-[3-(4-fluorophonyl)-4-methoxy-5-ethanesulfonylamino]phenylpiperazine

250 g of the title compound was prepared from 440 g of1-(t-butoxycarbonyl)-4-(3-bromo-4-methoxy-5-ethanesulfonyl)phenylpiperazinein a similar manner to that of the Example 9.

¹H-NMR(400 MHz, CDCl₃); δ(ppm) 7.6(2H, m), 7.4(1H, m), 7.2(2H, m),7.0(1H, m), 3.6(4H, m), 3.5(2H, q), 3.4(3H, s), 3.2(4H, m), 1.5(9H, s),1.3(3H, t).

Example 40

Synthesis of1-ethyl4-[3-(4-florophenyl)-4-methoxy-5-ethanesulfonylamino]phenylpiperazine

180 g of the title compound was prepared from 2.50 g of1-(t-butoxycarbonyl)-4-[3-(4-fluorophenyl)-4-methoxy-5-ethanesulfonyl]phenylpiperazinein a similar manner to that of the Example 12 or 13.

¹H-NMR(400 MHz, CDCl₃); δ(ppm) 7.6(2H, m), 7.4(1H, m), 7.2(2H, m),7.05(1H, m), 3.5(2H, q), 3.4(3H, s), 3.3(4H, m), 2.6(4H, m), 2.5(2H, q),1.3(3H, t), 1.1(3H, t).

Example 41

Synthesis of 1-[1-bromo-4-chloro-5-(1-hydroxypropyl)]phenylpiperazine

41.7 g (0.1 mol)1-(t-butoxycarbonyl)-4-[3-bromo-4-chloro-5-(1-hydroxypropyl)]phenylpiperazinewas dissolved in 100 ml of 10% hydrochloric acid/ethanol. The obtainedsolution was stirred at room temperature one whole day and night andthen distilled to remove the solvent. The obtained residue waspartitioned between ethyl acetate and a saturated aqueous solution ofsodium hydrogen carbonate. The organic phase was dehydrated anddistilled to remove the solvent, giving 30 g of the title compound as acolorless oil (in a yield of 95%).

¹H-NMR(400 MHz, CDCl₃); δ(ppm) 7.1(2H, m), 5.0(1H, m), 3.3(4H, m),3.1(4H, m), 1.7(2H, m), 1.0(3H, t).

Example 42

Synthesis of1-(2-hydroxyethyl)-4-[3-bromo-4-chloro-5-(1-hydroxypropyl)]phenylpiperazine

30 g (0.095 mol) of1-[3-bromo-4-chloro-5-(1-hydroxypropyl)]phenylpiperazine was dissolvedin 100 ml of dry DMF, followed by the addition of 20 g of potassiumcarbonate and 12.5 g (0.1 mol) of bromoethanol. The obtained mixture wasstirred at 50° C. one whole day and night and then partitioned betweenethyl acetate and water. The organic phase was dehydrated andconcentrated under reduced pressure. The residue was purified by columnchromatography (with methylene chloride/methanol) to give 17.1 g of thetitle compound as a colorless oil (in a yield of 50%).

¹H-NMR(400 MHz, CDCl₃); δ(ppm) 7.1(2H, m), 5.0(1H, m), 3.6(2H, m),3.2(4H, m), 2.7(4H, m), 2.6(2H, m), 1.7(2H, m), 1.0(3H, t).

Example 43

Synthesis of 1-[3-bromo-4-chloro-5-(1-fluoropropyl)]phenylpiperazine

38 g (0.09 mol) of1-(t-butoxycarbonyl)-4-[3-bromo-4-chloro-5-(1-fluoropropyl)]phenylpiperazineprepared in Example 8 was dissolved in 10% hydrochloric acid/ethanol.The obtained solution was stirred at room temperature one whole day andnight and then distilled to remove the solvent. The residue waspartitioned between ethyl acetate and a saturated aqueous solution ofsodium hydrogen carbonate. The organic phase was dehydrated anddistilled to remove the solvent, giving 28.9 g of the title compound asa colorless oil (in a yield of 100%).

¹H-NMR(400 MHz, CDCl₃); δ(ppm) 7.1(1H, d), 7.0(1H, d), 5.7(1H, m),3.2(4H, m), 3.1(4H, m), 1.9(2H, m), 1.0 (931, t).

Example 44

Syntnesis of1-(2-hydroxyethyl)-4-[3-bromo-4-chloro-5-(1-fluoropropyl)]phenylpiperazine

28.9 g (0.09 mol) of1-[3-bromo-4-chloro-5-(1-fluoropropyl)]phenylpiperazine was dissolved in50 ml, of dry DMF, followed by the addition of 18.6 g (0.135 mol) ofpotassium carbonate and 12.5 g (0.1 mol) of bromoethanol. The obtainedmixture was stirred at 50° C. one whole day and night. Ethyl acetate andwater were added to the reaction mixture to conduct partition. Theorganic phase was dehydrated and concentrated under reduced pressure.The obtained residue was purified by column chromatography (withmethylene chloride/methanol) to give 22.8 g of the title compound as acolorless oil (in a yield of 70%).

¹H-NMR(400 MHz, CDCl₃); δ(ppm) 7.1(1H, d), 7.0(1H, d), 5.7(1H, m),3.6(2H, m), 3.2(4H, m), 2.7(4H, m), 2.6(2H, m), 1.9(2H, m), 1.0(3H, t).

The following compounds were each prepared in a similar manner to thatdescribed above.

Example 45

1-Ethyl-4-(3-phenyl-4-methoxy-5-chloromelthy)phenylpiperazine

¹H-NMR(400 MHz, CDCl₃); δ(ppm) 7.55(2H, m), 7.45(2H, m), 7.4(1H, m),7.1(1H, m), 6.95(1H, m), 4.75(2H, s), 3.7(4H, m), 3.3(3H, s),3.2-3.0(6H, m), 1.25(3H, t).

Example 46

1-Ethyl-4-{3-phenyl-4-methoxy-5-[1-fluoro-(4-pentenyl)]}phenylpiperazine

¹H-NMR(400 MHz, CDCl₃); δ(ppm) 7.6(2H, d), 7.4(3H, m), 7.0(1H, s),6.9(1H, s), 5.9(1H, m), 5.8(1H, m), 5.0(2H, m), 3.3(3H, s), 3.2(4H, m),2.6(4H, m), 2.5(2H, q), 2.2(4H, m), 1.1(3H, t). Mass; MH⁺ 383.

Example 47

1-Ethyl-4-[3-phenyl-4-methoxy-5-(1-fluorobutyl)]phenylpiperazine

¹H-NMR(400 MHz, CDCl₃); δ(ppm) 7.6(2H, d), 7.4(3H, m), 7.0(1H, d),6.8(1H, d), 5.8(1H, m), 3.3(3H, s), 3.2(4H, m), 2.6(4H, m), 2.5(2H, q),1.9(2H, m), 1.5(2H, m), 1.1(3H, t), 1.0(3H, t).

Example 48

1-Ethyl-4-[3-phenyl-4-methoxy-5-(1-fluoropentyl)]phenylpiperazine

¹H-NMR(400 MHz, CDCl₃); δ(ppm) 7.6(2H, d), 7.4(3H, m), 7.0(1H, d),6.8(1H, d), 5.8(1H, m), 3.3(3H, s), 3.2(4H, m), 2.6(4H, m), 2.5(2H, q),2.0(2H, m), 1.4(4H, m), 1.1(3H, t), 0.9(3H, t).

Example 49

1-Ethyl-4-[3-(2-tolyl)-4-chloro-5-(1-fluorobutyl)]phenylpiperazine

¹H-NMR(400 MHz, CDCl₃); δ(ppm) 7.3-7.1(5H, m), 6.7(1H, d), 5.8(1H, m),3.2(4H, m), 2.6(4H, m), 2.5(2H, q), 2.1(3H, d), 1.9(2H, m), 1.6(4H, m),1.1(3H, t), 1.0(3H, t).

Example 50

1-Ethyl-4-[3-(2-tolyl)-4-fluoro-5-(1-fluorobutyl)]phenylpiperazine

¹H-NMR(400 MHz, CDCl₃); δ(ppm) 7.2 (4H, m), 7.0(1H, m), 6.7(1H, m),5.8(1H, m), 3.2(4H, m), 2.6(4H, m), 2.5(2H, q), 2.2(3H, s), 1.8(4H, m),1.1(3H, t), 1.0(3H, t). Mass; MH⁺ 373.

Example 51

1-Ethyl-4-[3-(2-tolyl)-4-chloro-5-(1-fluoro-3-methylbutyl)]phenylpiperazine

¹H-NMR(400 MHz, CDCl₃); δ(ppm) 7.3-7.0(5H, m), 6.7(1H, d), 5.9(1H, m),3.2(4H, m), 2.6(4H, m), 2.4(2H, q), 2.1(3H, m), 2.0-1.6(3H, m), 1.1(3H,m), 1.0(6H, d-t). Mass; MH⁺ 403.

Example 52

1-Ethyl-4-[3-(2-tolyl-4-chloro-5-(1-fluoroethyl)]phenylpiperazine

¹H-NMR(400 MHz, CDCl₃); δ(ppm) 7.3-7.1(5H, m), 6.7(1H, m), 6.0(1H, m),3.2(4H, m), 2.6(4H, m), 2.5(2H, q), 2.1(3H, m), 1.6(3H, m), 1.1(3H, t).Mass; MH⁺ 361.

Example 53

1-Methyl-4-[3-(2-tolyl)-4-chloro-5-(1-fluorobutyl)]phenylpiperazine

¹H-NMR(400 MHz, CDCl₃); δ(ppm) 7.3(3H, m), 7.1(2H, m), 6.7(1H, m),5.8(1H, m), 3.2(4H, m), 2.6(4H, m), 2.4(3H, s), 2.1(3H, d), 1.9(2H, m),1.6(2H, m), 1.0(3H, m).

Example 54

1-Ethyl-4-[3-(2-chlorophenyl)-4-chloro-5-(1-fluorobutyl)]phenylpiperazine

¹H-NMR(400 MHz, CDCl₃); δ(ppm) 7.3(4H, m), 7.1(1H, m), 6.8(1H, m),5.8(1H, m), 3.2(4H, m), 2.6(4H, m), 2.5(2H, q), 1.9(2H, m), 1.6(2H, m),1.1(3H, t), 1.0(3H, t).

Example 55

1-Ethyl-4-[3-(2-tolyl)-4-chloro-5-(1,1-difluoropropyl)]phenylpiperazine

¹H-NMR(400 MHz, CDCl₃); δ(ppm) 7.4-7.1(5H, m), 6.8(1H, d), 3.2(4H, m),2.6(4H, m), 2.5-2.3(4H, m), 2.1(3H, s), 1.1(3H, t), 1.0(3H, t).

Example 56

1-Ethyl-4-(3,5-diphenyl-4-methoxy)phenylpiperazine

¹H-NMR(400 MHz, CDCl₃); δ(ppm) 7.6(4H, m), 7.4(4H, m), 7.35(2H, m),6.9(2H, s), 3.25(4H, m), 3.0(3H, s), 2.6(4H, m), 2.5(2H, q), 1.1(3H, t).

Example 57

1-Ethyl-4-(3-phenyl-4-methoxy)phenylpiperazine

¹H-NMR(400 MHz, CDCl₃); δ(ppm) 7.5(2H, m), 7.4(2H, m), 7.3(1H, m),7.0(1H, m), 6.9(1H, m), 3.75(3H, s), 3.2(4H, m), 2.6(4H, m), 2.45(2H,q), 1.1(3H, t).

Example 58

1-Ethyl-4-(3,5-diphenyl-4-hydroxy)phenylpiperazine

¹H-NMR(400 MHz, CDCl₃); δ(ppm) 7.6(4H, m), 7.45(4H, m), 7.4(2H, m),6.9(2H, s), 3.2(4H, m), 2.6(4H, m), 2.5(2H, q), 1.1(3H, t).

Example 59

1-Ethyl-4-(3-phenyl-4-methoxy-5-propyl)phenylpiperazine

¹H-NMR(400 MHz, CDCl₃); δ(ppm) 7.6(2H, d), 7.42(2H, m), 7.3(1H, m),6.8(2H, m), 3.3(3H, s), 3.2(4H, m), 2.6(4H, m), 2.6(2H, t), 2.5(2H, q),1.6(2H, m), 1.15(3H, t), 1.0(3H, t).

Example 60

1-Ethyl-4-(3,5-diphenyl-4-isopropxy)phenylpiperazine

¹H-NMR(400 MHz, CDCl₃); δ(ppm) 7.6(4H, d), 7.4(4H, m), 7.3(2H, m),6.9(2H, s), 3.4(1H, m), 3.25(4H, m), 2.6(4H, m), 2.5(2H, q), 1.1(3H, t),1.6(6H, d).

Example 61

1-Ethyl-4-(3-phenyl-4-isopropxy)phenylpiperazine

¹H-NMR(400 MHz, CDCl₃); δ(ppm) 7.6(4H, d), 7.4(2H, m), 7.3(1H, m),7.0-6.0(3H, m), 4.2(1H, m), 3.2(4H, m), 2.6(4H, m), 2.45(2H, q), 1.2(3H,t).

Example 62

1-Ethyl-4-(3-phenyl-4-hydroxy)phenylpiperazine

¹H-NMR(400 MHz, CDCl₃); δ(ppm) 7.5(4H, m), 7.4(1H, m), 6.9(2H, m),6.85(1H, m), 3.15(4H, m), 2.6(4H, m), 2.5(2H, q), 1.1(3H, t).

Example 63

1-Ethyl-4-[2-methoxy-3-phenyl-5-(3-hydroxypropyl)]phenylpiperazine

¹H-NMR(400 MHz, CDCl₃); δ(ppm) 7.60(2H, d), 7.40(2H, m), 7.35(1H, m),6.8(2H, s), 3.6(2H, t), 3.3(3H, s), 3.2(4H, m), 2.8(2H, t), 2.6(5H, m),2.5(2H, q), 1.9(2H, m), 1.1(3H, t).

Example 64

1-(2-Hydroxyethyl-)4-(3,5-diphenyl-4-(methoxy)phenylpiperazine

¹H-NMR(400 MHz, CDCl₃); δ(ppm) 7.6(4H, m), 7.4(4H, m), 7.35(2H, m),6.9(2H, s), 3.65(2H, m), 3.2(4H, m), 3.1(3H, s), 2.7(4H, m), 2.6(2H, t).

Example 65

1-Ethyl-4-[3-(4-florophenyl)4-methoxy-5-propyl)]phenylpiperazine

¹H-NMR(400 MHz, CDCl₃); δ(ppm) 7.6(2H, m), 7.1(2H, m), 6.75(2H, m),3.3(3H, s), 3.2(4H, m), 2.6(4H, m), 2.45(2H, q), 1.65(2H, m), 1.1(3H,t), 1.0(3H, t).

Example 66

1-Ethyl-4-[3-phenyl-4-methoxy-5-(2-hydroxyethyl)]phenylpiperazine

¹H-NMR(400 MHz, CDCl₃); δ(ppm) 7.6(2H, m), 7.4(2H, m), 7.3(1H, m),6.8(2H, m), 3.8(2H, t), 3.3(3H, s), 3.2(4H, m), 3.1(2H, t), 2.6(4H, m),2.5(2H, q), 1.1(3H, t).

Example 67

1-Ethyl-4-[2-methoxy-3-phenyl-5-(2-hydroxyethyl)]phenylpiperazine

¹H-NMR(400 MHz, CDCl₃); δ(ppm) 7.6(2H, m), 7.4(2H, m), 7.35(1H, m),6.8(2H, s), 3.9(2H, t), 3.3(3H, s), 3.2(4H, m), 2.9(2H, t), 2.6(4H, m),2.5(2H, m), 1.1(3H, t).

Example 68

1-Ethyl-4-[3-phenyl-4-methoxy-5-(3-methoxypropyl)]phenylpiperazine

¹H-NMR(400 MHz, CDCl₃); δ(ppm) 7.6(2H, d), 7.4(2H, t), 7.3(1H, m),6.8(2H, m), 3.45(2H, m), 3.40(3H, s), 3.30(3H, s), 3.20(4H, m), 2.7(2H,t), 2.6(4H, m), 2.5(2H, q), 1.9(2H, m), 1.1(3H, t).

Example 69

1-Ethyl-4-[3-phenyl-4-methoxy-5-(3-methoxymethoxypropyl)]phenylpiperazine

¹H-NMR(400 MHz, CDCl₃); δ(ppm) 7.6(2H, d), 7.4(2H, m), 7.35(1H, m),6.8(2H, m), 3.6(2H, t), 3.4(3H, s), 3.3(3H, s), 3.2(4H, m), 2.8(2H, m),2.6(4H, m), 2.5(2H, q), 2.0(2H, m), 1.1(3H, t).

Example 70

1-Ethyl-4-(3-phenyl-4-methoxy-5-ethyl)]phenylpiperazine

¹H-NR(400 MHz, CDCl₃); δ(ppm) 7.6(2H, d), 7.4(2H, m), 7.35(1H, m),6.8(2H, m), 3.3(3H, s), 3.2(4H, m), 2.7(2H, q), 2.6(4H, m), 2.5(2H, q),1.25(3H, t), 1.1(3H, t).

Example 71

1-Ethyl-4-[3-phenyl-4-methoxy-5-(3-cyanopropyl)]phenylpiperazine

¹H-NMR(400 MHz, CDCl₃); δ(ppm) 7.6(2H, d), 7.4(2H, m), 7.35(1H, m),6.8(2H, m), 3.3(3H, s), 3.2(4H, m), 2.8(2H, t), 2.6(4H, m), 2.5(2H, q),2.4(2H, t), 2.0(2H, m), 1.1(3H, t).

Example 72

1-(2-Fluoroethyl)-4-[3-(4-fluorophenyl)-4-methoxy-5-propyl]phenylpiperazine

¹H-NMR(400 MHz, CDCl₃); δ(ppm) 7.6(2H, m), 7.1(2H, m), 6.75(2H, m),4.6(2H, d-t), 3.3(3H, s), 3.2(4H, m), 2.7(4H, m), 2.7(2H, m), 1.7(2H,m), 1.0(3H, t).

Example 73

1-Ethyl-4-[3-(4-methoxphenyl)-4-methoxy-5-propyl]phenylpiperazine

¹H-NMR(400 MHz, CDCl₃); δ(ppm) 7.5(2H, m), 6.95(2H, m), 6.75(2H, m),3.85(3H, s), 3.3(3H, s), 3.2(4H, m), 2.6(4H, m), 2.45(2H, q), 1.7(2H,m), 1.1(3H, t), 1.0(3H, t).

Example 74

1-Ethyl-4-(3-phenyl-4-methoxy-5-methoxycarbonyl)phenylpiperazine

¹-NMR(400 MHz, CDCl₃); δ(ppm) 7.6(2H, d), 7.4(2H, m), 7.33(1H, m),7.0(1H, m), 3.95(3H, s), 3.4(3H, s), 3.2(4H, m), 2.6(4H, m), 2.5(2H, q),1.1(3H, t).

Example 75

1-Ethyl-4-[3-phenyl-4-methoxy-5-(2-hydroxypropyl)]phenylpiperazine

¹H-NMR(400 MHz, CDCl₃); δ(ppm) 7.6(2H, d), 7.4(2H, m), 7.35(1H, m),6.8(2H, s), 4.1(1H, m), 3.3(3H, s), 3.2(4H, m), 3.0(1H, b-s), 2.8(2H,m), 2.6(4H, m), 2.4(2H, q), 1.25(3H, d), 1.1(3H, t).

Example 76

1-Ethyl-4-[3-phenyl-4-methoxy-5-(2-fluoroetheyl)]phenylpiperazine

¹H-NMR(400 MHz, CDCl₃); δ(ppm) 7.6(2H, d), 7.4(2H, m), 7.35(1H, m),6.8(2H, m), 4.75(2H, t), 4.6(2H, t), 3.3(3H, s), 3.2(4H, m), 3.1(2H, t),3.05(2H, t), 2.6(4H, m), 2.5(2H, q), 1.15(3H, t).

Example 77

1-Ethyl-4-[3-phenyl-4-methoxy-5-(3-fluoropropyl)]phenylpiperazine

¹H-NMR(400 MHz, CDCl₃); δ(ppm) 7.6(2H, d), 7.4(2H, m), 7.35(1H, m),6.8(2H, s), 4.6(2H, t), 4.45(2H, t), 3.3(3H, s), 3.2(4H, m), 2.8(2H, m),2.6(4H, m), 2.5(1H, q), 2.05(2H, m), 1.15(3H, t).

Example 78

1Ethyl-4-[3-(4-fluorophenyl)-4-methoxy-5-isopropyl]phenylpiperazine

¹H-NMR(400MHz, CDCl₃); δ(ppm) 7.55(2H, m), 7.1(2H, m), 6.8(1H, m),6.7(1H, m), 3.4(1H, m), 3.3(3H, s), 3.2(4H, m), 2.6(4H, m), 2.5(2H, q),1.25(6H, s), 1.1(3H, t).

Example79

1Ethyl-4-[3-(4-fluorophenyl)-4-metheyl-6-isopropyl]phenylpiperazine

^(1H-NMR()400 MHz, CDCl₃); δ(ppm) 7.55(2H, m), 7.4(1H, m), 7.1(2H, m),6.85(1H, m), 3.8(3H, s), 3.6(1H, m), 2.9(4H, m), 2.5(2H, q), 1.55(4H,b-s), 1.25(6H, d), 1.1(3H, t).

Example 80

1Ethyl-4-[3-phenyl-4-methoxy-5-(1-methyl-hydroxyisoropyl]phenylpiperazine

¹H-NMR(400 MHz, CDCl₃); δ(ppm) 7.6(2H, d), 7.4(2H, m), 7.35(1H, m),6.95(1H, m), 6.8(1H, m), 3.3(3H, s), 3.2(4H, m), 2.6(4H, m), 2.45(2H,q), 1.6(6H, s), 1.1(3H, t).

Example 81

1-Ethyl-4-[3-phenyl-4-methoxy-5-(1-butoxypropyl]phenylpiperazine

¹H-NMR(400 MHz, CDCl₃); δ(ppm) 7.6(2H, m), 7.4(2H, m), 7.35(1H, m),7.0(1H, d), 6.8(1H, m), 4.6(1H, m), 3.4(1H, m), 3.35(1H, m), 3.3(3H, s),3.2(4H, m), 2.6(4H, m), 2.5(2H, q), 1.75(2H, m), 1.6(2H, m), 1.4(2H, m),1.1(3H, t), 1.0(3H, t), 0.9(3H, t).

Example 82

1-Ethyl-4-(3-phenyl-4methoxy-5-propionyl)phenylpiperazine

¹H-NMR(400 MHz, CDCl₃); δ(ppm) 7.55(2H, m), 7.4(3H, m), 7.0(2H, m),3.3(3H, s), 3.2(4H, m), 3.0(2H, q), 2.6(4H, m), 3.42(2H, q), 1.2(3H, t),1.1(3H, t).

Example 83

1-Ethyl-4-[3-phenyl-4methoxy-5-(1-hydroxypropyl)]phenylpiperazine

¹H-NMR(400 MHz, CDCl₃); δ(ppm) 7.5(2H, m), 7.35(3H, m), 7.0(1H, m),6.7(1H, m), 4.9(1H, m), 4.0(1H, b-s), 3.25(3H, s), 3.2-3.0(4H, m),2.6(4H, m), 2.45(2H, m), 1.8(2H, m), 1.1(3H, t), 1.0(3H, t).

Example 84

1-Ethyl-4-[3-(2-fluorophenyl)-4-methoxy-5-propyl]phenylpiperazine

¹H-NMR(400 MHz, CDCl₃); δ(ppm) 7.4-7.3(2H, m), 7.2-7.1(2H, m), 6.8(1H,d), 6.7(1H, d), 3.3(3H, s), 3.2(4H, m), 2.6(6H, m), 2.5(2H, q), 1.7(2H,m), 1.15(3H, t), 1.0(3H, t).

Example 85

1-Ethyl-4-[3-(4-trifluoromethylphenyl)-4-methoxy-5-propyl]phenylpiperazine

¹H-NMR(400 MHz, CDCl₃); δ(ppm) 7.7(4H, m), 6.8(1H, m), 6.7(1H, m),3.3(3H, s), 3.2(4H, m), 2.6(6H, m), 2.45(2H, q), 1.7(2H, m), 1.15(3H,t), 1.0(3H, t).

Example 86

1-Ethyl-4-[3-phenyl-4-methoxy-5-(1-fluoroisopropyl)]phenylpiperazine

¹H-NMR(400 MHz , CDCl₃); δ(ppm) 7.55(2H, m), 7.4(3H, m), 7.1(1H, d),6.8(1H, d), 3.2(3H, s), 3.2(4H, m), 2.6(4H, m), 2.5(2H, q), 1.8(6H, d),1.15(3H, t).

Example 87

1-Ethyl-4-[3-phenyl-4-methoxy-5-(2-hydroxyisoproply)]phenylpiperzine

¹H-NMR(400 MHz, CDCl₃); δ(ppm) 7.6(2H, d), 7.4(2H, t), 7.35(1H, m),6.8(2H, m), 3.75(2H, d), 3.4(1H, m), 3.3(3H, s), 3.2(4H, m), 2.6(4H, m),2.5(2H, q), 1.95(2H, m), 1.6(2H, m), 1.3(3H, d), 1.1(3H, t).

Example 88

1-Ethyl-4-[3-phenyl-4-methoxy-5-(1-fluoropropyl)]phenylpiperazine

¹H-NMR(400 MHz, CDCl₃); δ(ppm) 7.6(2H, m), 7.4(3H, m), 7.0(1H, m),6.85(1H, m), 5.75(1H, m), 3.3(3H, s), 3.2(4H, m), 2.6(4H, m), 2.5(2H,q), 2.0(2H, m), 1.15(3H, t), 1.05(3H, t).

Example 89

1-Ethyl-4-(3-phenyl-4-methoxy-5-cyano)phenylpiperazine

¹H-NMR(400 MHz, CDCl₃); δ(ppm) 7.5(2H, m), 7.4(3H, m), 7.1(1H, d),7.1(1H, d), 3.6(3H, s), 3.2(4H, m), 2.6(4H, m), 2.5(2H, q), 1.1(3H, t).

¹H-NMR(400 MHz, CDCl₃); δ(ppm) 7.6(2H, m), 7.5-7.3(5H, m), 7.0(1H, d),6.8(1H, d), 6.5(1H, d), 3.3(3H, s), 5.25(4H, m), 2.6(4H, m), 2.5(2H, q),1.2(3H, t).

Example 91

1-Ethyl-4-[3-(2,4-difluorophenyl)-4-methoxy-5-propyl]phenylpiperazine

¹H-NMR(400 MHz, CDCl₃); δ(ppm) 7.4(1H, m), 7.0-6.9(2H, m), 6.8(1H, m),6.65(1H, m), 3.3(3H, s), 3.2(4H, m), 2.6(6H, m), 2.5(2H, q), 1.7(2H, m),1.15(3H, t), 1.0(3H, t).

Example 92

1-Ethyl-4-(3-phenyl-4-methoxy-5-phenylacetyl)phenylpiperazine

¹H-NMR(400 MHz, CDCl₃); δ(ppm) 7.6(2H, d), 7.45-7.2 (8H, m), 7.0(2H, s),4.35(2H, s), 3.35(3H, s), 3.2(4H, m), 2.6(4H, m), 2.45(2H, m), 1.1(3H,t).

Example 93

1-Ethyl-4-[3-phenyl-4-methoxy-5-(4-fluorophenyl)acetyl]phenylpiperazine

¹H-NMR(400 MHz, CDCl₃); δ(ppm) 7.6(2H, d), 7.4(3H, m), 7.25(2H, m),7.0(4H, m), 4.3(2H, s), 3.35(3H, s), 3.2(4H, m), 2.6(4H, m), 2.45(2H,q), 1.1(3H, t).

Example 94

1-Etyl-4-[3-phenyl-4-methoxy-5-(1-hydroxyphenethyl)]phenylpiperazine

¹H-NMR(400 MHz, CDCl₃); δ(ppm) 7.6(2H, m), 7.4-7.2(8H, m), 7.0(1H, m),6.8(1H, m), 5.2(1H, m), 3.3(3H, s), 3.2(4H, m), 3.0(1H, m), 2.6(4H, m),2.5(2H, q), 1.1(3H, t).

Example 95

1-Ethyl-4-[3-phenyl-4-methoxy-5-(2-tetrahydrofuranyl)]phenylpiperazine

¹H-NMR(400 MHz, CDCl₃); δ(ppm) 7.6(2H, m), 7.4(2H, t), 7.35(1H, t),7.0(1H, s), 6.8(1H, s), 5.2(1H, t), 4.1(1H, m), 3.95(1H, m), 3.3(3H, s),3.2(4H, m), 2.6(4H, m), 2.5(2H, m), 2.0(2H, m), 1.8(2H, m), 1.15(3H, t).

Example 96

1-Ethyl-4-[3-phenyl-4-methoxy-5-(1-fluorophenethyl)]phenylpiperazine

¹H-NMR(400 MHz, CDCl₃); δ(ppm) 7.6(2H, d) 7.4-7.2(8H, m), 6.95(1H, m),6.85(1H, m), 6.0(1H, m), 3.25(3H, s), 3.2(4H, m), 2.6(4H, m), 2.5(2H,q), 1.1(3H, t).

Example 97

1-Ethyl-4-[3-phenyl-4-methoxy-5-(2-pyridyl)]phenylpiperazine

¹H-NMR(400 MHz, CDCl₃); δ(ppm) 8.7(1H, m), 7.8(1H, d), 7.7(1H, t),7.6(2H, d), 7.4(2H, t), 7.35(1H, m), 7.3(1H, d), 7.0(1H, d), 3.3(4H, m),3.2(3H, s), 2.6(4H, m), 2.5(2H, q), 1.1(3H, t).

Example 98

1-Ethyl-4-{3-phenyl-4-methoxy-5-[4-fluoro-(1-hydroxyimino)phentheyl]}phenylpiperazine

¹H-NMR(400 MHz, CDCl₃); δ(ppm) 7.55(2H, m) 7.4(3H, m), 7.1(2H, m),6.9(2H, m), 6.7(2H, m), 4.2(2H, s), 3.3(3H, s), 3.2(4H, m), 2.65(4H, m),2.5(2H, m), 1.2(3H, t).

Example 99

1-Ethyl-4-{3-phenyl-4-methoxy-5-[1-fluoro-2-(2-pyridyl)ethyl]}phenylpiperazine

¹H-NMR(400 MHz, CDCl₃); δ(ppm) 8.6(1H, m), 7.6(3H, m), 7.4(2H, m),7.35(1H, m), 7.25(1H, m), 7.15(1H, m), 7.05(1H, m), 6.9(1H, m), 6.25(1H,m), 3.4(2H, m), 3.3(3H, s), 3.2(4H, m), 2.6(4H, m), 2.5(2H, q), 1.15(3H,t).

Example 100

1-Ethyl-4-[3-phenyl-4-methoxy-5-(1-propenyl)]phenylpiperazinehydrochloroide

¹H-NMR(400 MHz, CDCl₃); δ(ppm) 7.95(1H, m), 7.6(6H, m), 7.5(2H, m),7.4(3H, m), 6.7(1H, d), 6.45(1H, m), 4.75(2H, t), 4.3(2H, m), 3.7(4H,m), 3.4(3H, s), 3.2(2H, m), 2.0(3H, d), 1.5(3H, t).

Example 101

1-Ethyl-4-[3-(3-fluorophenyl)-4-methoxy-5-propyl]phenylpiperazine

¹H-NMR(400 MHz, CDCl₃); δ(ppm) 7.4-7.2)3H, m), 7.0(1H, m), 6.75(2H, m),3.3(3H, s), 3.2(4H, m, 2.6(6H, m), 2.45(2H, q), 1.7(2H, m), 1.1(3H, t),1.0(3H, t).

Example 102

1-Ethyl-4-(3-phenyl-4-methoxy-5-hydroxymethyl)phenylpiperazine

¹H-NMR(400 MHz, CDCl₃); δ(ppm) 7.6(2H, m), 7.4(3H, m), 6.9(1H, m),6.8(1H, m), 4.7(2H, s), 3.35(3H, s), 3.2(4H, m), 2.65(4H, m), 2.5(2H,q), 1.2(3H, t).

Example 103

1-Ethyl-4-[3-phenyl-4-methoxy-5-(4-pyridyl)acetyl]phenylpiperazine

¹H-NMR(400 MHz, CDCl₃); δ(ppm) 8.6(2H, m), 7.6(2H, m), 7.4(3H, m),7.2(2H, d), 7.05(2H, m), 4.4(2H, s), 3.35(3H, s), 3.2(4H, m), 2.6(4H,m), 2.5(2H, q), 1.1(3H, t).

Example 104

1-Ethyl-4-(3-phenyl-4-methoxy-5-methanesulfinyl)phenylpiperazine

¹H-NMR(400 MHz, CDCl₃); δ(ppm) 7.6(2H, d), 7.4(4H, m), 6.95(1H, d),3.35(3H, s), 3.3(4H, m), 2.9(3H, s), 2.6(4H, m), 2.5(2H, q), 1.05(3H,t).

Example 105

1-Ethyl-4-(3-phenyl-4-methoxy-5-ethanesulfinyl)phenylpiperazine

¹H-NMR(400 MHz, CDCl₃); δ(ppm) 7.6(2H, m), 7.4(3H, m), 7.3(1H, m),6.95(1H, m), 3.35(3H, s), 3.3(4H, m), 3.15(2H, m), 2.9(2H, m), 2.6(4H,m), 2.5(2H, m), 1.3(3H, t), 1.15(3H, t),

Example 106

1-Ethyl-4-(3-phenyl-4-methoxy-5-formyl)phenylpiperazine

¹H-NMR(400 MHz, CDCl₃); δ(ppm) 10.43(1H, s), 7.34-7.6(5H, m), 7.17(2H,m), 3.46(3H, s), 3.40(1H, m), 2.81(4H, m), 2.66(2H, q), 1.25(3H, t).

Example 107

1-Ethyl-4-[3-phenyl-4-methoxy-5-(1,3-dioxan-2yl)]phenylpiperazine

¹H-NMR(400 MHz, CDCl₃); δ(ppm) 7.3-7.54(5H, m), 7.18(1H, d), 6.89(1H,d), 5.85(1H, s), 4.26(2H, d-d), 4.04(2H, d-t), 3.34(3H, s), 3.25(4H, m),2.62(4H, m), 2.51(2H, q), 2.25(1H, m), 1.45(1H, m), 1.15(3H, t).

Example 108

Ethyl-4-(3-phenyl-4-methoxy-5-cyclopropaneacetyl)phenylpiperazine

¹H-NMR(400 MHz, CDCl₃); δ(ppm) 7.6(2H, d), 7.4(3H, m), 7.0(2H, m),5.9(1H, m), 5.1(2H, m), 3.35(3H, s), 3.2(4H, m), 3.15(2H, t), 2.6(4H,m), 2.45(4H, m), 1.1(3H, t).

Example 109

1-Ethyl-4-[3-phenyl-4-methoxy-5-(2-pyridylcarbonyl)]phenylpiperazine

¹H-NMR(400 MHz, CDCl₃); δ(ppm) 8.7(1H, m), 8.05(1H, d), 7.85(1H, m),7.6(2H, m), 7.4(3H, m), 7.35(1H, m), 7.05(1H, m), 7.0(1H, m), 3.2(4H,m), 3.1(3H, s), 2.66(4H, m), 2.5(2H, q), 1.1(3H, t).

Example 110

1-Ethyl-4-(3-phenyl-4-methoxy-5-amino)phenylpiperazine

¹H-NMR(400 MHz, CDCl₃); δ(ppm) 7.6(2H, m), 7.4-7.3(3H, m), 6.35(1H, m),6.3(1H, m), 3.9(2H, b-s), 3.7(2H, q), 3.35(3H, s), 3.2(4H, m), 2.6(4H,m), 2.45(2H, q), 1.2(3H, t), 1.1(3H, t).

Example 111

1-Ethyl-4-[3-phenyl-4-methoxy-5-(2-ethoxycarbonylethyl)]phenylpiperazine

¹H-NMR(400 MHz, CDCl₃); δ(ppm) 7.3-7.59(5H, m), 6.78(2H, m), 4.14(2H,q), 3.30(3H, s), 3.21(4H, m), 2.97(2H, t), 2.65(2H, t), 2.62(4H, m),2.50(2H, q), 1.25(3H, t), 1.14(3H, t).

Example 112

1-Ethyl-4-[3-phenyl-4-methoxy-5-(2-pyridyl)hydroxymethyl]phenylpiperazine

¹H-NMR(400 MHz, CDCl₃); δ(ppm) 8.6(1H, m), 7.65(1H, t), 7.6(2H, m),7.4(3H, m), 7.35(1H, m), 7.2(1H, m), 6.9(1H, m), 6.8(1H, m), 3.3(3H, s),3.2(4H, m), 2.5(4H, m), 2.4(2H, q), 1.1(3H, t).

Example 113

1-Ethyl-4-(3-phenyl-5-propyl-6-methoxy)phenylpiperazine hyrochloroide

¹H-NMR(400 MHz, CDCl₃); δ(ppm) 13.5(1H, b-s), 8.05(1H, m), 7.6(2H, m),7.5(1H, s), 7.45(2H, t), 7.4(1H, t), 4.8(2H, m), 4.4(2H, b-s), 4.2(3H,s), 3.8(2H, d), 3.6(2H, d), 3.25(2H, b-s), 2.8(2H, t), 1.75(2H, m),1.6(3H, b-s), 1.0(3H, t).

Example 114

1-Ethyl-4-[3-phenyl-4-methoxy-5-(2-acetylethyl)]phenylpiperazine

¹H-NMR(400 MHz, CDCl₃); δ(ppm) 7.30-7.59(5H, m), 6.75(2H, s), 3.28(3H,s), 3.19(4H, m), 2.89(2H, m), 2.82(2H, m), 2.61(4H, m), 2.47(2H, q),2.17(3H, s), 1.12(3H, t).

Example 115

1-Ethyl-4-{3-phenyl-4-methoxy-5-[1-(2-pyridylmethoxy)propyl]}phenylpiperazine

¹H-NMR(400 MHz, CDCl₃); δ(ppm) 8.7(1H, d), 8.2(1H, t), 7.85(1H, d),7.6(1H, t), 7.5(2H, m), 7.4(1H, m), 7.35(1H, m), 7.1(1H, s), 6.8(2H, s),4.8(3H, m), 3.6(6H, m), 3.25(3H, s), 3.15(2H, q), 3.0(2H, m), 1.9(2H,m), 1.5(3H, t), 1.0(3H, t).

Example 116

1-Ethyl-4-[3-(2-tolyl)-4-methoxy-5-propyl]phenylpiperazine

¹H-NMR(400 MHz, CDCl₃); δ(ppm) 7.18-7.25(4H, m), 6.78(1H, d), 6.59(1H,d), 3.24(3H, s), 3.18(4H, m), 2.58-2.62(6H, m), 2.48(2H, q), 2.19(3H,s), 1.66(2H, m), 1.13(3H, t), 0.99(3H, t).

Example 117

1-Ethyl-4-(3-phenyl-4-methoxy-5-propylamino)phenylpiperazine

¹H-NMR(400 MHz, CDCl₃); δ(ppm) 7.6(2H, m), 7.4(2H, t), 7.3(1H, m),6.25(1H, d), 6.2(1H, d), 4.3(1H, b-s), 3.3(3H, s), 3.2(4H, m), 3.1(2H,t), 2.6(4H, m), 2.5(2H, q), 1.7(2H, m), 1.1(3H, t), 1.0(3H, t).

Example 118

1-(3-Phenyl-4-hyroxy-5-phenylaectyl)phenylpiperazine

¹H-NMR(400 MHz, CDCl₃); δ(ppm) 7.55(2H, d), 7.4-7.25(5H, m), 4.3(2H, s),3.2(8H, m).

Example 119

1-Ethyl-4-(3-phenyl-4-methoxy-5-benzylsulfinyl)phenylpiperazine

¹H-NMR(400 MHz, CDCl₃); δ(ppm) 7.6(2H, d), 7.5-7.35(4H, m), 7.25(2H, m),7.1(2H, m), 6.9(2H, m), 4.2(2H, q), 3.4(3H, s), 3.1(4H, m), 2.55(4H, m),2.45(2H, q), 1.1(3H, t).

Example 120

1-Ethyl-4-(3-phenyl-4-methoxy-5-benzenesulfinylamino)phenylpiperazine

¹H-NMR(400 MHz, CDCl₃); δ(ppm) 7.8(2H, m), 7.6-7.3(8H, m), 7.2(1H, d),6.6(1H, d), 3.2(4H, m), 2.9(3H, s), 2.6(4H, m), 2.5(2H, q), 1.55(3H, t).

Example 121

1-Ethyl-4-{3-phenyl-4-methoxy-5-[1-fluoro-2-(4-pyridyl)ethyl]}phenylpiperazine

¹H-NMR(400 MHz, CDCl₃); δ(ppm) 8.5(2H, d), 7.6(2H, m), 7.4(2H, m),7.35(1H, m), 7.2(2H, d), 6.85(2H, m), 5.95(1H, m), 3.2(3H, s), 3.15(4H,m), 2.6(4H, m), 2.4(2H, q), 1.1(3H, t).

Example 122

1-Ethyl-4-[3-phenyl-4-methoxy-5-(N-ethanesulfonyl-N-methylamino)]phenylpiperazine

¹H-NMR(400 MHz, CDCl₃); δ(ppm) 7.6(1H, m), 7.5(2H, m), 7.4(3H, m),6.8(1H, d), 3.7(2H, m), 3.4(3H, s), 3.2(4H, m), 2.6(4H, m), 2.5(2H, q),1.25(3H, t), 1.15(3H, t).

Example 123

1-Ethyl-4-(3-phenyl-4-methoxy-5-ethylaminofonyl)phenylpiperazine

¹H-NMR(400 MHz, CDCl₃); δ(ppm) 7.55(2H, d), 7.4(4H, m), 7.0(1H, d),5.0(1H, t), 3.4(3H, s), 3.25(4H, m), 3.05(2H, q), 2.6(4H, m), 2.5(2H,q), 1.15(3H, t).

Example 124

1-Ethyl-4-(3-phenyl-4-methoxy-5-aminosulfonyl)phenylpiperazine

¹H-NMR(400 MHz, CDCl₃); δ(ppm) 7.55(2H, d), 7.4(4H, m), 7.0(1H, d),5.4(2H, s), 3.4(3H, s), 3.2(4H, m), 2.6(4H, m), 2.45(2H, q), 1.1(3H, s).

Example 125

1-(3-phenyl-4-methoxy-5-phenylacetyl)phenylpiperazine

¹H-NMR(400 MHz, CDCl₃); δ(ppm) 7.6(2H, d), 7.5-7.2(8H, m), 7.0(2H, s),4.4(2H, s), 3.35(3H, s), 3.1(4H, m), 3.0(4H, m).

Example 126

1-Benzyl-4-(3-phenyl-4-methoxy-5-phenylacetyl)phenylpiperazine

¹H-NMR(400 MHz, CDCl₃); δ(ppm) 7.6(2H, d), 7.45-7.2(8H, m), 7.0(2H, s),4.35(2H, s), 3.6(2H, s), 3.35(3H, s), 3.2(4H, m), 2.6(4H, m).

Example 127

1-Ethyl-4-[3-phenyl-4-chloro-5-(1-fluoropropyl)]phenylpiperazine

¹H-NMR(400 MHz, CDCl₃); δ(ppm) 7.4(5H, m), 7.05(1H, d), 6.8(1H, d),5.8(1H, m), 3.25(4H, m), 2.6(4H, m), 2.5(2H, q), 2.0(2H, m), 1.15(3H,t), 1.05(3H, t).

Example 128

1-(2-Hydroxyethyl)-4-(3-phenyl-4-methoxy-5-phenylacetyl)phenylpiperazine

¹H-NMR(400 MHz, CDCl₃); δ(ppm) 7.6(2H, d) 7.5-7.2(8H, m), 7.0(2H, s),4.4(2H, s), 3.65(2H, t), 3.35(3H, s), 3.2(4H, m), 2.65(4H, m), 2.6(2H,t).

Example 129

1-Ethyl-4-[3-phenyl-5-(1-fluoropropyl)]phenylpiperazine

¹H-NMR(400 MHz, CDCl₃); δ(ppm) 7.6(2H, d), 7.4(2H, m), 7.35(1H, m),7.05(1H, s), 6.9(1H, s), 5.4(1H, m), 3.3(4H, m), 2.6(4H, m), 2.5(2H, q),2.0(2H, m), 1.15(3H, t), 1.0(3H, t).

Example 130

1-Ethyl-4-(3-phenyl-5-propionyl)phenylpiperazine

¹H-NMR(400 MHz, CDCl₃); δ(ppm) 7.6(2H, d), 7.6-7.3(7H, m), 3.3(4H, m),3.0(2H, q), 2.6(4H, m), 2.5(2H, q), 1.2(3H, t), 1.1(3H, t).

Example 131

1-Ethyl-4-[3-(2-tolyl)-4-chloro-5-(1-fluoropropyl)]phenylpiperazine

¹H-NMR(400 MHz, CDCl₃); δ(ppm) 12.9(1H, b-s), 7.4-7.2(3H, m), 7.1(2H,m), 6.8(1H, s), 5.8(1H, m), 3.8-3.6(6H, m), 3.2(2H, b-s), 3.0(2H, b-s),2.1(3H, d), 1.9(2H, m), 1.5(3H, t), 1.05(3H, t).

Example 132

1-Ethyl-4-[3-(2-methoxyphenyl)-4-methoxy-5-propyl)]phenylpiperazine

¹H-NMR(400 MHz, CDCl₃); δ(ppm) 7.3(2H, m), 7.0(2H, m), 6.75(2H, m),3.8(3H, s), 3.3(3H, s), 3.2(4H, m), 2.6(6H, m), 2.45(2H, q), 1.7(2H, m),1.15(3H, t), 1.0(3H, t).

Example 132

1-Ethyl-4-(3-phenyl-4-methoxy-5-ethanesulfonyl)phenylpiperazine

¹H-NMR(400 MHz, CDCl₃); δ(ppm) 7.6(2H, d), 7.4(4H, m), 7.1(1H, d),3.5(2H, q), 3.4(3H, s), 3.25(4H, m), 2.6(4H, m), 2.5(2H, q), 1.3(3H, t),1.1(3H, t).

Example 134

1-Ethyl-4-(3-phenyl-4-methoxy-5-dimemthylaminosulfonyl)phenylpiperazine

¹H-NMR(400 MHz, CDCl₃); δ(ppm) 7.6(2H, d), 7.5-7.3(4H, m), 7.0(1H, d),3.4(3H, s), 3.2(4H, m), 2.95(6H, s), 2.6(4H, m, 2.5(2H, q), 1.15(3H, t).

Example 135

1-Ethyl-4-[3-phenyl-4-methoxy-5-(1-pyrrolidinylsulfonyl)]phenylpiperazine

¹H-NMR(400 MHz, CDCl₃); δ(ppm) 7.55(2H, m), 7.4(4H, m), 7.0(1H, d),3.45(4H, m), 3.4(3H, s), 3.25(4H, m), 2.6(4H, m), 2.5(2H, q), 1.9(4H,m), 1.15(3H, t).

Example 136

1-Ethyl-4-[3-(2-tolyl)-4-chloro-5-(2,2,2-trifluoroethyl)sulfonylamino)]phenylpiperazine

¹H-NMR(400 MHz, CDCl₃); δ(ppm) 7.4-7.2(4H, m), 7.1(1H, m), 6.6(1H, m),5.1(1, b-s), 3.85(2H, q), 3.2(4H, m), 2.65(4H, m), 2.6(2H, q), 2.1(3H,s), 1.2(3H, t).

Example 137

1-Ethyl-4-[3-(2-tolyl)-4-chloro-5-(4-fluorophenylsulfonylamino)]phenylpiperazine

¹H-NMR(400 MHz, CDCl₃); δ(ppm) 7.8(2H, m) 7.3-7.1(4H, m), 7.1(2H, m),7.0(1H, d), 6.55(1H, s), 3.2(4H, m), 2.6(4H, m), 2.5(2H, q), 1.85(3H,s), 1.1(3H, t).

Example 138

1Ethyl-4-[3-phenyl-4-chloro-5-(1-hydroxypropyl)]phenylpiperazine

¹H-NMR(400 MHz, CDCl₃); δ(ppm) 7.27-7.43(5H, m), 7.16 (1H, d), 6.62(1H,d), 5.06 (1H, d-d), 3.12(2H, m), 2.95(2H, m), 2.56(4H, m), 2.38-2.54(2H,m), 1.64-1.83(2H, m), 1.17(3H, t), 1.02(3H, t).

Example 139

1Ethyl-4-(3-phenyl-4-chloro-5-ethanesulfonyl)phenylpiperazine

¹H-NMR(400 MHz, CDCl₃); δ(ppm) 7.7(1H, d) 7.5-7.4(5H, m), 7.0(1H, m),3.5(2H, q), 3.3(4H, m), 2.6(4H, m), 2.5(2H, q), 1.35(3H, t), 1.15(3H,t).

Example 140

1-Ethyl-4-(3-phenyl-4-chloro-5-propionyl)phenylpiperazine

¹H-NMR(400 MHz, CDCl₃); δ(ppm) 7.30-7.43(5H, m), 6.89(1H, d), 6.80(1H,d), 3.22(4H, m), 2.94(2H, q), 2.58(4H, m), 2.45(2H, q), 1.22(3H, t),1.11(3H, t).

Example 141

1-Ethyl-4-[3-(2tolyl-4-chloro-5-(1-pyrrolidylsulfonyl)]phenylpiperazine

¹H-NMR(400 MHz, CDCl₃); δ(ppm) 7.7(1H, d), 7.4-7.2(3H, m), 7.1(1H, d),6.8(1H, m), 3.4(4H, m), 3.3(4H, m), 2.45(2H, q), 2.1(3H, s), 1.9(4H, m),1.1(3H, t).

Example 142

1-Ethyl-4-{3-[2-(4-fluorotolyl)]-4-chloro-5-(1-fluoropropyl)}phenylpiperazine

¹H-NMR(400 MHz, CDCl₃); δ(ppm) 7.1-7.0(2H, m), 7.0-6.9(2H, m), 6.7(1H,d), 5.8(2H, m), 3.2(4H, m), 2.6(4H, m), 2.45(2H, q), 1.9(2H, m), 2.1(3H,d), 1.1(3H, t), 1.05(3H, m).

Example 143

1-Ethyl-4-[3-(2-methoxyphenyl)-4-chloro-5-(1-fluoropropyl)]phenylpiperazine

¹H-NMR(400 MHz, CDCl₃); δ(ppm) 7.4(1H, m), 7.2(1H, m), 7.0(3H, m),6.8(1H, d), 5.8(1H, m), 3.8(3H, s), 3.25(4H, m), 2.6(4H, m), 2.5(2H, q),1.15(3H, t), 1.05(3H, t).

Example 144

1-Ethyl-4-[3-(2,4-difluorophenyl)-4-chloro-5-(1-fluoropropyl)]phenylpiperazine

¹H-NMR(400 MHz, CDCl₃); δ(ppm) 7.2(1H, m), 7.1(1H m), 7.0-6.9(2H, m),6.8(1H, m), 5.8(1H, m), 3.2(4H, m), 2.6(4H, m), 2.45(2H, q), 1.9(2H, m),1.1(3H, t), 1.05(3H, m).

Example 145

1-Ethyl-4-[3-(2-methoxymethylphenyl)-4-chloro-5-(1-fluoropropyl)]phenylpiperazine

¹H-NMR(400 MHz, CDCl₃); δ(ppm) 7.55(1H, m), 7.4(1H, m), 7.3(1H, m),7.2(1H, m), 7.05(1H, m), 6.8(1H, m), 5.7(1H, m), 4.3-4.1(2H, m), 3.3(4H,m), 3.25(3H, d), 2.7(4H, m), 2.55(2H, m), 2.0(2H, m), 1.2(3H, t),1.05(3H, t).

Example 146

1-Ethyl-4-{3-[2(4-fluorotolyl)-]4-chloro-5-cyclopropaneaminosulfonyl}phenylpiperazine

¹H-NMR(400 MHz, CDCl₃); δ(ppm) 7.75(1H, s), 7.1-6.8(5H, m), 5.55(1H, s),3.3(4H, m), 2.6(4H, m), 2.5(2H, q), 2.2(1H, m), 2.1(3H, s), 1.1(3H, t),0.7-0.6(4H, m).

Example 147

1-Ethyl-4-[3-phenyl-4-chloro-5-(1-methylpropyl)]phenylpiperazine

¹H-NMR(400 MHz, CDCl₃); δ(ppm) 7.4(5H, m), 6.69(2H, d), 6.65(2H, d),3.18-3.30(1H, m), 3.18(4H, m), 2.60(4H, m), 2.48(2H, m), 1.17-1.92(2H,m), 1.2(3H, d), 1.12(3H, t), 0.89(3H, t).

Example 148

1-Ethyl-4-{3-[2(4-fluorotolyl)]-4-chloro-5-cyclopropylmethylsulfonyl}phenylpiperazine

¹H-NMR(400 MHz, CDCl₃); δ(ppm) 7.75(1H, d), 7.05(1H, m), 7.0-6.9(3H, m),3.4(2H, d), 3.3(4H, m), 2.6(4H, m), 2.5(2H, q), 2.1(3H, s), 1.1(3H, t),1.0(1H, m), 0.6(2H, m), 0.25(2H, m).

Example 149

1-Ethyl-4-(3-phenyl-4-fluoro-5-ethanesulfonyl)phenylpiperazine

NMR(CDCl₃) d; 7.55-7.4(5H, m), 7.2(1H, m), 3.35(2H, q), 3.25(4H, m),2.6(4H, m), 2.5(2H, q), 1.3(3H, t), 1.1(3H, t).

Example 150

1-[3[(4-pyridyl)propyl]-4-[3-(2-tolyl)-4-chloro-5-(1-fluoropropyl)]phenylpiperazine

¹H-NMR(400 MHz, CDCl₃); δ(ppm) 8.48(2H, d), 7.20-7.32(4H, m), 7.1(2H,d), 7.02(1H, d), 6.71(1H, d), 5.78(1H, d-t), 3.22(4H, m), 2.68(2H, t),2.60(4H, m), 2.41(2H, t), 2.12(2H, q), 2.08(3H, d), 1.80-1.94(2H, m),1.07(3H, d-t).

Example 151

1-Propyl-4-[3-(2-tolyl)-4-chloro-5-(1-fluoropropyl)]phenylpiperazine

¹H-NMR(400 MHz, CDCl₃); δ(ppm) 7.1-7.28(4H, m), 7.02(1H, d), 6.70(1H, d)5.78(1H, d-t), 3.22(4H, m), 2.59(4H, m), 2.37(2H, d-d), 2.11(3H, d),1.8-1.96(2H, m ), 1.5-1.6(2H, m), 1.06(3H, d-t), 0.92(3H, t).

Example 152

1-Ethyl-4-[3-(2-hydroxymethylphenyl)-4-chloro-5-(1-fluoropropyl)]phenylpiperazine

¹H-NMR(400 MHz, CDCl₃); δ(ppm) 7.6(1H, m), 7.45(1H, m), 7.35(1H, m),7.2(1H, d), 7.05(1H, d), 6.75(1H, d), 5.75(1H, m), 4.5-4.4(2H, m),3.25(4H, m), 2.6(4H, m), 2.5(2H, q), 1.9(2H, m), 1.15(3H, t), 1.05(3H,t).

Example 153

1-Ethyl-4-[3-(2-tolyl)-4-chloro-5-propanesulfonylamino]phenylpiperazine

¹H-NMR(400 MHz, CDCl₃); δ(ppm) 7.4(1H, t), 7.4-7.2(3H, m), 7.2-7.6(2H,m), 3.2(4H, m), 3.1(2H, d-d,) 2.6(4H, m), 2.5(3H, s), 2.45(2H, q),1.8(2H, m), 1.1(3H, t), 1.0(31, t).

Example 154

1-Ethyl-4-[3-(2-tolyl)-4-chloro-5-dimethylaminosulfonyl]phenylpiperazine

¹H-NMR(400 MHz, CDCl₃); δ(ppm) 7.65(1H, t), 7.3-7.2(3H, m), 7.1(1H, m),6.9(1H, d), 3.25(4H, m), 2.9(6H, s), 2.6(4H, m), 2.45(2H, q), 2.1(3H,s), 1.1(3H, t).

Example 155

1-Ethyl-4-[3-(2-tolyl)-4-chloro-5-methanesulfonyl]phenylpiperazine

¹H-NMR(400 MHz, CDCl₃); δ(ppm) 7.4(1H, m), 7.4-7.2(4H, m), 7.0(1H, m),3.25(4H, m), 3.2(3H, s), 2.6(4H, m), 2.5(2H, q), 2.2(3H, s), 1.1(3H, t).

Example 156

1-Ethyl-4-[3-(2-chloro-4-fluorophenyl)-4-chloro-5-methanesulfonyl]phenylpiperazine

¹H-NMR(400 MHz, CDCl₃); δ(ppm) 7.4(2H, m), 7.0(2H, m), 6.7(1H, m),5.8(1H, m), 3.2(4H, m), 2.6(4H, m), 2.45(2H, q), 2.0(2H, m), 1.1(3H, t),1.05(3H, m).

Example 157

1-Ethyl-4-[3-(2-tolyl)-4-chloro-5-(1-ethylpropyl)]phenylpiperazine

¹H-NMR(400 MHz, CDCl₃); δ(ppm) 7.06-7.24(4H, m), 6.74(1H, d), 6.61(1H,d), 3.20(4H, m), 3.15(1H, m), 2.60(4H, m), 2.46(2H, q), 2.00(3H, s),1.23(3H, t), 1.56-1.74(4H, m), 0.78(3H, t), 0.76(3H, t).

Example 158

1-Ethyl-4-[3-(2-tolyl)-4-chloro-5-methanesulfonyl]phenylpiperazine

¹H-NMR(400 MHz, CDCl₃); δ(ppm) 7.7(1H, d), 7.3(3H, m), 7.1(1H, m),6.95(1H, d), 3.3(3H, s), 3.3(4H, m), 2.6(4H, m), 2.45(2H, q), 2.1(3H,s), 1.1(3H, t).

Example 159

1-Ethyl-4-[3-(2-tolyl)-4-chloro-5-propanesulfonyl]phenylpiperazine

¹H-NMR(400 MHz, CDCl₃); δ(ppm) 7.75(1H, m), 7.4-7.2(3H, m), 7.1(1H, d),6.95(1H, d), 3.4(2H, m), 3.3(4H, m), 2.6(4H, m), 2.45(2H, q), 2.1(3H,s), 1.8(2H, m), 1.1(3H, t), 1.0(3H, t).

Example 160

1-Ethyl-4-[3-(2-tolyl)-4-chloro-5-(1-fluoro-4-pentenyl)]phenylpiperazine

¹H-NMR(400 MHz, CDCl₃); δ(ppm) 7.3-7.2(4H, m), 7.15(1H, m), 7.05(1H, m),5.9-5.8(1H, m), 5.1-5.0(2H, m), 3.2(4H, m), 2.6(4H, m), 2.45(2H, q),2.3(2H, m), 2.1(3H, m), 2.0(2H, m), 1.1(3H, t).

Example 161

1-Ethyl-4-[3-(2-tolyl)-4-chloro-5-propylaminosulfonyl]phenylpiperazine

¹H-NMR(400 MHz, CDCl₃); δ(ppm) 7.75(1H, d), 7.4-7.2(3H, m), 7.1(1H, d),6.9(1H, d), 5.1(1H, t), 3.3(4H, m), 2.95(2H, q), 2.6(4H, m), 2.45(2H,q), 2.1(3H, s), 1.5(2H, m), 1.1(3H, t), 0.9(3H, t).

Example 162

1-Ethyl-4-[3-(2-tolyl)-4-chloro-5-ethanesulfonylamino]phenylpiperazine

¹H-NMR(400 MHz, CDCl₃); δ(ppm) 7.7(1H, m), 7.45(1H, m), 7.25(3H, m),7.1(1H, m), 3.2(4H, m), 3.15(2H, q), 2.6(4H, m), 2.45(2H, q), 2.1(3H,s), 1.4(3H, t), 1.1(3H, t).

Example 163

1-Ethyl-4-[3-(2-chlorophenyl)-4-chloro-5-(2,2,2-trifluoroethyl)sulfonylamino]phenylpiperazine

¹H-NMR(400 MHz, CDCl₃); δ(ppm) 7.7(2H, m), 7.5(2H, m), 7.4(2H, m),6.65(1H, d), 3.9(2H, q), 3.2(4H, m), 2.6(4H, m), 2.5(2H, q), 1.1(3H, t).

Example 164

1-Ethyl-4-[3-(2-tolyl)-4-cyano-5-(1-fluoropropyl)]phenylpiperazine

¹H-NMR(400 MHz, CDCl₃); δ(ppm) 7.3-7.2(4H, m), 7.0(1H, m), 6.65(1H, d),5.75(1H, m), 3.4(4H, m), 2.6(4H, m), 2.45(2H, q), 2.2(3H, d), 2.0(2H,m), 1.1(3H, t), 1.05(3H, t).

Example 165

1-Ethyl-4-[3-(2-tolyl)-4-chloro-5-(3-chlorophenyl)sulfonyamino]phenylpiperazine

¹H-NMR(400 MHz, CDCl₃); δ(ppm) 7.7(2H, m), 7.55(1H, m), 7.45(2H, m),7.3(1H, m), 3.6(2H, t), 3.2(4H, m), 2.6(4H, m), 2.45(2H, m), 2.3(2H, m),2.1(3H, s), 1.1(3H, t).

Example 166

1-Ethyl-4-[3-(2-tolyl)-4-chloro-5-phenylaminosulfony]phenylpiperazine

¹H-NMR(400 MHz, CDCl₃); δ(ppm) 7.55(1H, d), 7.4-7.0(9H, m), 6.8(1H, d),3.2(4H, m), 2.55(4H, m), 2.4(2H, q), 2.0(3H, s), 1.1(3H, t).

Example 167

1-Ethyl-4-[3-(2-tolyl)-4-chloro-5-benzyloxymethyl]phenylpiperazine

¹H-NMR(400 MHz, CDCl₃); δ(ppm) 7.65(1H, m), 7.6-7.1(9H, m), 6.7(1H, d),4.65(2H, s), 3.2(4H, m), 2.6(4H, m), 2.45(2H, q),2.1(3H, t), 1.1(3H, t).

Example 168

1-Ethyl-4-[3-(2-tolyl)-4-chloro-5-propoxymethyl]phenylpiperazine

¹H-NMR(400 MHz, CDCl₃); δ(ppm) 7.65(1H, m), 7.45(1H, m), 7.3-7.2(2H, m),7.1(1H, m), 6.7(1H, d), 4.6(2H, s), 3.6(2H, t), 3.2(4H, m), 2.6(4H, m),2.45(2H, q), 2.1(3H, s), 1.7(2H, m), 1.1(3H, t), 1.0(3H, t).

Example 169

1-Ethyl-4-[3-(2-tolyl)-4-chloro-5-(4-pyridyl)methoxymethyl]phenylpiperazine

¹H-NMR(400 MHz, CDCl₃); δ(ppm) 8.6(2H, m), 7.4-7.2(5H, m), 7.15(2H, m),6.75(1H, d), 4.71(2H, s), 4.70(2H, s), 3.2(4H, m), 2.6(4H, m), 2.45(2H,q), 2.1(3H, s), 1.1(3H, t).

Example 170

1-Ethyl-4-(3-phenyl-4-methoxy-5-propanesulfonyl)phenylpiperazine

¹H-NMR(400 MHz, CDCl₃); δ(ppm) 7.6(1H, d), 7.4(4H, m), 7.1(1H, m),3.45(2H, m), 3.4(3H, s), 3.25(4H, m), 2.6(4H, m), 2.5(2H, q), 1.8(2H,m), 1.15(3H, t), 1.0(3H, t).

Example 171

1-Ethyl-4-(3-phenyl-4-methoxy-5-butanesulfonyl)phenylpiperazine

¹H-NMR(400 MHz, CDCl₃); δ(ppm) 7.55(1H, d), 7.4(4H, m), 7.1(1H, d),3.45(2H, m), 3.4(3H, s), 3.2(4H, m), 2.6(4H, m), 2.5(2H, q), 1.75(2H,m), 1.4(2H, m), 1.1(3H, t), 0.95(3H, t).

Example 172

1-Ethyl-4-[3-phenyl-4-methoxy-5-(2-fluoroethane)sulfonyl]phenylpiperazine

¹H-NMR(400 MHz, CDCl₃); δ(ppm) 7.55(1H, d), 7.4(4H, m), 7.1(1H, m),4.9(1H, t), 4.8(1H, t), 3.95(1H, t), 3.85(1H, t), 3.4(3H, s), 3.25(4H,m), 2.6(4H, m), 2.5(2H, q), 1.1(3H, t).

Example 173

1-Ethyl-4-[3-(2-tolyl)-4-chloro-5-ethoxymethyl]phenylpiperazine

¹H-NMR(400 MHz, CDCl₃); δ(ppm) 7.7(1H, m), 7.45(1H, m), 7.25(1H, m),7.1(2H, m), 6.7(1H, m), 4.6(2H, s), 3.65(2H, q), 3.2(4H, m), 2.6(4H, m),2.45(2H, q), 2.1(3H, s), 1.3(3H, t), 1.1(3H, t).

Example 174

1-Methyl-4-[3-(2-tolyl)-4-chloro-5-(1-hydroxybutyl]phenylpiperazine

¹H-NMR(400 MHz, CDCl₃); δ(ppm) 7.3-7.1(5H, m), 65.6(1H, m), 5.15(1H, m),3.2(4H, m), 2.6(4H, m), 2.35(3H, s), 2.1(3H, d), 1.8-1.4(4H, m), 1.0(3H,t).

Example 175

1-Ethyl-4-[3-(2-tolyl)-4-chloro-5-allyloxymethyl]phenylpiperazine

¹H-NMR(400 MHz, CDCl₃); δ(ppm) 7.25(3H, m), 7.1(2H, m), 6.7(1H, d),6.0(1H, m), 5.3(2H, m), 4.6(2H, s), 4.2(2H, m), 3.2(4H, m), 2.6(4H, m),2.45(2H, q), 2.1(3H, s), 1.1(3H, t).

Example 176

1-Ethyl-4-[3-(2-tolyl)-4-chloro-5-cyclopropylmethoxymethyl]phenylpiperazine

¹H-NMR(400 MHz, CDCl₃); δ(ppm) 7.25(3H, m), 7.1(2H, m), 6.7(1H, d),4.6(2H, s), 3.4(2H, d), 3.2(4H, m), 2.6(4H, m), 2.45(2H, q), 2.1(3H, s),1.25(1H, m), 1.1(3H, t), 0.6(2H, m), 0.25(2H, m).

Example 177

1-Ethyl-4-[3-(2-tolyl)-4-chloro-5-(1-pyrrolidinyl]phenylpiperazine

¹H-NMR(400 MHz, CDCl₃); δ(ppm) 7.18-7.28(4H, m), 6.21(1H, d), 6.10(1H,d), 3.51(4H, m), 3.26(4H, m), 2.61(1H, d), 2.48(2H, q), 2.30(3H, s),1.99(4H, m), 1.14(3H, t).

Example 178

1-Methyl-4-[3-(2-chlorophenyl)-4-chloro-5-(1-fluorobutyl)]phenylpiperazine

¹H-NMR(400 MHz, CDCl₃); δ(ppm) 7.45(1H, m) 7.3(3H, m), 7.1(1H, d),6.75(1H, d), 5.5(1H, m), 3.2(4H, m), 2.6(4H, m), 2.35(3H, s), 1.9(2H,m), 1.6(2H, m), 1.0(3H, t).

Example 179

1-Methyl-4-[3-(2-chlorophenyl)-4-chloro-5-benzylsulfonylamino]phenylpiperazine

¹H-NMR(400 MHz, CDCl₃); δ(ppm) 7.5(1H, m), 7.4(5H, m), 7.25(4H, m),6.6(1H, d), 4.4(2H, d-d), 3.2(4H, m), 2.6(4H, m), 2.4(3H, s).

Example 180

1-Methyl-4-[3-(2-chlorophenyl)-4-chloro-5-propanesulfonyl]phenylpiperazine

¹H-NMR(400 MHz, CDCl₃); δ(ppm) 7.7(1H, d), 7.5(1H, m), 7.4(2H, m), 7.25(1H, m), 7.0(1H, d), 3.5-3.4(2H, m), 3.3(4H, m), 2.6(4H, m), 2.4(3H, s),1.8(2H, m), 1.6(3H, s), 1.0(3H, t).

Example 181

1-Ethyl-4-{3-phenyl-4-methoxy-5-[3-(4-fluorophenoxy)propane]sulfonyl}phenylpiperazine

¹H-NMR(400 MHz, CDCl₃); δ(ppm) 7.55(2H, m), 7.4(3H, m), 7.1(1H, d),7.0(2H, m), 6.8(2H, m), 4.0(2H, t), 3.7(2H, d-d), 3.4(3H, s), 3.25(4H,m), 2.6(4H, m), 2.5(2H, q), 2.25(2H, m), 1.1(3H, t).

Example 182

1-Methyl-4-(3-(2-chlorophenyl)-4-chloro-5-isopropylsulfonylamino]phenylpiperazine

¹H-NMR(400 MHz, CDCl₃); δ(ppm) 7.41-7.46(2H, m) 7.30-7.38(2H, m),7.24(1H, m), 6.60(1H, d), 3.24(1H, m), 3.21(4H, m), 2.57(4H, m),2.35(3H, s), 1.96(6H, d).

Example 183

1-Ethyl-4-[3-phenyl-4-methoxy-5-(2-cycanoethylsulfonyl)]phenylpiperazine

¹H-NMR(400 MHz, CDCl₃); δ(ppm) 7.6(2H, m), 7.5-7.4(4H, m), 7.15(1H, d),3.8(2H, t), 3.4(3H, s), 3.25(4H, m), 2.85(2H, t), 2.6(4H, m), 2.5(2H,q), 1.15(3H, t).

Example 184

1-Ethyl-4-(3-phenyl-4-chloro-5-propanesulfonylamino)phenylpiperazine

¹H-NMR(400 MHz, CDCl₃); δ(ppm) 7.36-7.48(5H, m), 7.24(1H, d), 6.65(1H,d), 3.26(4H, m), 3.10(2H, m), 2.58(4H, m), 2.46(2H, q), 1.82-1.90(2H,m), 1.12(3H, t), 1.02(3H, t).

Example 185

1-Ethyl-4-[3-(2-tolyl)-4-chloro-5-difluoromethyl]phenylpiperazine

¹H-NMR(400 MHz, CDCl₃); δ(ppm) 7.4-7.2(4H, m), 7.1(1H, m), 6.85(1H, m),3.25(4H, m), 2.6(4H, m), 2.45(2H, q), 2.1(3H, s), 1.1(3H, t).

Example 186

1-Ethyl-4-[3-phenyl-4-methoxy-5-(1,1-difluoropropyl)]phenylpiperazine

¹H-NMR(400 MHz, CDCl₃); δ(ppm) 7.6(2H, m), 7.4(3H, m), 7.05(1H, d),6.95(1H, d), 3.25(3H, s), 3.2(4H, m), 2.6(4H, m), 2.5(2H, q), 2.4(2H,m), 1.15(3H, t), 1.0(3H, t).

Example 187

1-Ethyl-4-[3-(4-methoxyphenyl)-4-chloro-5-propanesulfonyamino]phenylpiperazine

¹H-NMR(400 MHz, CDCl₃); δ(ppm) 7.35(2H, m), 7.25(1H, m), 7.0(2H, m),6.65(1H, s), 3.85(3H, s), 3.25(4H, m), 3.1(2H, m), 2.6(4H, m), 2.45(2H,q), 1.85(2H, m), 1.1(3H, t), 1.0(3H, t).

Example 188

1-Methyl-4-[3-(2-chlorophenyl)-4-chloro-5-methanesulfonylamino]phenylpiperazine

¹H-NMR(400 MHz, CDCl₃); δ(ppm) 7.23-7.48(5H, m), 6.62(1H, d), 3.24(4H,m), 3.02(3H, s), 2.54(4H, m), 2.34(3H, s).

Example 189

1-Ethyl-4-[3-(2,4-dichlorophenyl)-4-chloro-5-propanesulfonyamino]phenylpiperazine

¹H-NMR(400 MHz, CDCl₃); δ(ppm) 7.7(2H, m), 7.5(2H, m), 7.3(1H, m),3.25(4H, m), 3.1(2H, m), 2.6(4H, m), 2.45(2H, q), 1.85(2H, m), 1.1(3H,t), 1.0(3H, t).

Example 190

1-Ethyl-4-[3-(2-tolyl)-4-chloro-5-(1,3-dithian-2-yl)phenylpiperazinepropanedithio]phenylpiperazine

¹H-NMR(400 MHz, CDCl₃); δ(ppm) 7.45(2H, d), 7.3-7.2(3H, m), 7.15(1H, d),6.7(1H, m), 6.1(1H, s), 3.5-3.3(4H, m), 3.2(4H, m), 2.6(4H, m), 2.1(3H,s), 1.1(3H, t).

Example 191

1-Ethyl-4-[3-phenyl-4-chloro-5-propanesulfonyl)]phenylpiperazine

¹H-NMR(400 MHz, CDCl₃); δ(ppm) 7.7(2H, m), 7.5-7.4(4H, m), 7.0(1H, d),3.4(2H, m), 3.3(4H, m), 2.6(4H, m), 2.45(2H, q), 1.8(2H, m), 1.15(3H,t), 1.0(3H, t).

Example 192

1-Ethyl-4-[3-(2-tolyl)-4-chloro-5-propanesulfonylaminomethyl]phenylpiperazine

¹H-NMR(400 MHz, CDCl₃); δ(ppm) 7.65(2H, m), 7.45(2H, m), 7.1(1H, m),6.6(1H, d), 3.2(4H, m), 3.1(2H, m), 2.6(4H, m), 2.45(2H, q), 2.1(3H, s),1.85(2H, m), 1.1(3H, t), 1.0(3H, t).

Example 193

1-Methyl-4-[3-(4-fluorophenyl)-4-methoxy-5-propanesulfonyl]phenylpiperazine

¹H-NMR(400 MHz, CDCl₃); δ(ppm) 7.55(2H, m), 7.4(1H, d), 7.2(2H, m),7.05(1H, d), 3.4(2H, m), 3.4(3H, s), 3.25(4H, m), 2.6(4H, m), 2.4(3H,s), 1.8(2H, m), 1.05(3H, t).

Example 194

1-Ethyl-4-[3-(2-ethylphenyl)-4-chloro-5-propanesulfonylamino]phenylpiperazine

¹H-NMR(400 MHz, CDCl₃); δ(ppm) 7.4-7.2(4H, m), 7.1(1H, d), 6.6(1H, d),3.25(4H, m), 3.1(2H, m), 2.6(4H, m), 2.5-2.3(4H, m), 1.85(2H, m),1.2-1.0(9H, m).

Example 195

1-(2-Hydroxyethyl)-4-[3-(4-florophenyl)-4-methoxy-5-ethanesulfonylamino]phenylpiperazine

¹H-NMR(400 MHz, CDCl₃); δ(ppm) 7.55(2H, m), 7.4(1H, d), 7.2(2H, m), 7.05(1H, d), 3.7(2H, t), 3.5(2H, q), 3.4(3H, s), 3.2(4H, m), 2.7(4H, m),2.6(2H, t), 1.3(3H, t).

Example 196

1-(2-Ethyl)-4-[3-(2-formylphenyl)-4-chloro-5-propanesulfonylamino]phenylpiperazine

¹H-NMR(400 MHz, CDCl₃); δ(ppm) 9.8(1H, s), 8.0(1H, d), 7.35(2H, m),6.6(1H, m), 3.3(4H, m), 3.1(2H, m), 2.6(4H, m), 2.5(2H, q), 1.9(2H, m),1.1(3H, t), 1.0(3H, t).

Example 197

1-Ethyl-4-[3-(2-cyanophenyl)-4-chloro-5-propanesulfonylamino]phenylpiperazine

¹H-NMR(400 MHz, CDCl₃); δ(ppm) 7.8(1H, d), 7.7(2H, m), 7.5(2H, m),6.6(1H, m), 3.3(4H, m), 3.1(2H, m), 2.6(4H, m), 2.5(2H, q), 1.9(2H, m),1.1(3H, t), 1.0(3H, t).

Example 198

1-[2-(2-Pyridyl)ethyl]-4-[3-(4-fluorophenyl)-4-methoxy-5-ethanesulfonyl]phenylpiperazine

¹H-NMR(400 MHz, CDCl₃); δ(ppm) 8.6(1H, m), 7.6(1H, m) 7.55(2H, m),7.4(1H, d), 7.2(1H, d), 7.15(3H, m), 7.05(1H, d), 3.5(2H, q), 3.4(3H,s), 3.25(4H, m), 3.0(2H, m), 2.8(2H, m), 2.7(4H, m), 1.3(1H, t).

Example 199

1-(2-Pyridylmethyl)-4-[3-(4-fluorophenyl)-4-methoxy-5-ethanesulfonyl]phenylpiperazine

¹H-NMR(400 MHz, CDCl₃); δ(ppm) 8.6(1H, m), 7.7(1H, m), 7.55(2H, m),7.4(2H, m), 7.2-7.1(3H, m), 7.05(1H, d), 3.75(2H, s), 3.5(2H, q),3.4(3H, s), 3.3(4H, m), 2.7(4H, m), 1.3(3H, t).

Example 200

1-(3-Pyridylmethyl)-4-[3-(4-fluorophenyl)-4-methoxy-5-ethanesulfonyl]phenylpiperazine

¹H-NMR(400 MHz, CDCl₃); δ(ppm) 8.6(1H, s), 8.55(1H, m), 7.7(1H, m),7.55(2H m), 7.4(1H, d), 7.3(1H, m), 7.2(2H, m), 7.0(1H, d), 3.6(2H, s),3.5(2H, q), 3.4(3H, s), 3.2(4H, m), 2.6(4H, m), 1.3(3H, t), 1.2(3H, t).

Example 201

1-[2-(4-Pyridyl)ethyl]-4-[3-(4-fluorophenyl)-4-methoxy-5-ethanesulfonyl]phenylpiperazine

¹H-NMR(400 MHz, CDCl₃); δ(ppm) 8.5(2H, m), 7.55(2H, m), 7.45(1H, d),7.2(4H, m), 7.05(1H, d), 3.5(2H, q), 3.4(3H, s), 3.25(4H, m), 2.8(2H,m), 2.7(6H, m), 1.3(3H, t), 1.2(3H, t).

Example 202

1-[3-(4-Fluorophenyl)-4-methoxy-5-ethanesulfonyl]phenylpiperazine

¹H-NMR(400 MHz, CDCl₃); δ(ppm) 7.55(2H, m), 7.45(1H, s), 7.2(2H, m),7.05(1H, d), 3.9(1H, b-s), 3.5(2H, q), 3.4(3H, s), 3.25(4H, m), 3.1(4H,m), 1.3(3H, t).

Example 203

1-(2-Fluoroethyl)-4-[3-(4-fluorophenyl)-4-methoxy-5-ethanesulfonyl]phenylpiperazine

¹H-NMR(400 MHz, CDCl₃); δ(ppm) 7.55(2H, m), 7.4(1H, m), 7.15(2H, m),7.05(1H, d), 4.6(2H, m), 3.5(2H, q), 3.4(3H, s), 3.25(4H, m), 2.75(2H,d-t), 2.7(4H, m), 1.3(3H, m).

Example 204

1-Ethyl-4-[3-(2-chlorophenyl)-4-chloro-5-(1-propenyl]phenylpiperazine

¹H-NMR(400 MHz, CDCl₃); δ(ppm) 7.5(1H, m), 7.3(3H, m), 7.05(1H, m),6.8(1H, m), 6.7(1H, d), 6.2(1H, m), 3.2(4H, m), 2.6(4H, m), 2.5(2H, q),1.95(3H, d), 1.15(3H, t).

Example 205

1-Ethyl-4-[3-(2-chlorophenyl)-4-chloro-5-(1-chlorophenyl0phenylpiperazine)]phenylpiperazine

¹H-NMR(400 MHz, CDCl₃); δ(ppm) 7.46(1H, m), 7.17-7.36(4H, m), 6.73(1H,d), 5.40(1H, m), 3.23(4H, m), 2.60(4H, m), 2.46(2H, d), 2.02-2.13(2H,m), 1.13(3H, t), 1.08(3H, t).

Example 206

1-Methyl-4-[3-phenyl-4-chloro-5-(1-fluorophenyl)]phenylpiperazine

¹H-NMR(400 MHz, CDCl₃); δ(ppm) 7.4(5H, m), 7.05(1H, d), 6.8(1H, s),5.8(1H, m), 3.2(4H, m), 2.6(4H, m), 2.35(3H, s), 2.0(2H, m), 1.05(3H,t).

Example 207

1-Methyl-4-[3-(2-hydroxymethylphenyl)-4-chloro-5-(1-fluorophenyl)]phenylpiperazine

¹H-NMR(400 MHz, CDCl₃); δ(ppm) 7.6(1H, m), 7.4(1H, t), 7.35(1H, m),7.2(1H, d), 7.05(1H, d), 6.75(1H, d), 5.75(1H, m), 4.45(2H, m), 3.2(4H,m), 2.6(4H, m), 2.3(3H, s), 2.0(2H, m), 1.05(3H, t).

Example 208

1-Ethyl-4-[3-(2-fluoromethylphenyl)-4-chloro-5-(1-fluoropropyl)]phenylpiperazine

¹H-NMR(400 MHz, CDCl₃); δ(ppm) 7.6(1H, m), 7.4(2H, m), 7.2(1H, d),7.05(1H, d), 6.8(1H, d), 5.75(1H, m), 5.3-5.0(2H, m), 3.2(4H, m),2.6(4H, m), 2.45(2H, q), 2.0(2H, m), 1.1(3H, t), 1.05(3H, t).

Example 209

1-Methyl-4-{3-(2-fluoromethylphenyl)-4-chloro-5-[1-(R)-fluorophenyl]}phenylpiperazine

¹H-NMR(400 MHz, CDCl₃); δ(ppm) 7.6(1H, m), 7.4(2H, m), 7.2(1H, d),7.05(1H, d), 6.8(1H, d), 5.75(1H, m), 5.3-5.0(2H, m), 3.2(4H, m),2.6(4H, m), 2.35(3H, s), 1.9(2H, m), 1.05(3H, t).

Example 210

1-Methyl-4-{3-(2-fluoromethylphenyl)-4-chloro-5-[1-(S)-fluoropropyl]}phenylpiperazine

¹H-NMR(400 MHz, CDCl₃); δ(ppm) 7.6(1H, m), 7.4(2H, m), 7.2(1H, d),7.05(1H, d), 6.8(1H, d), 5.75(1H, m), 5.3-5.0(2H, m), 3.2(4H, m),2.6(4H, m), 2.35(3H, s), 1.9(2H, m), 1.05(3H, t).

Example 211

1-Ethyl-4-{3-[2-(4-fluorotolyl)]-4-chloro-5-[1-(S)-fluoropropnyl]}phenylpiperazine

¹H-NMR(400 MHz, CDCl₃); δ(ppm) 7.1-7.0(2H, m), 7.0-6.9(2H, m), 6.7(1H,d), 5.75(1H, m), 3.25(4H, m), 2.6(4H, m), 2.5(2H, q), 2.1(3H, d),1.15(3H, t), 1.05(3H, m).

Example 212

1-Ethyl-4-{3-[2-(4-fluorotolyl)]-4-chloro-5-[1-(R)-fluorophenyl]}phenylpiperazine

¹H-NMR(400 MHz, CDCl₃); δ(ppm) 7.1-7.0(2H, m), 7.0-6.9(2H, m), 6.7(1H,d), 5.75(1H, m), 3.25(4H, m), 2.6(4H, m), 2.5(2H, q), 2.1(3H, d),1.15(3H, t), 1.05(3H, m).

Example 213

1-[2-(2-Pyridyl)ethyl]-4-[3-(2-tolyl)-4-chloro-5-(1-fluoropropyl)]phenylpiperazine

¹H-NMR(400 MHz, CDCl₃); δ(ppm) 8.55(1H, d), 7.6(1H, m), 7.3-7.2(4H, m),7.1(2H, m), 7.05(1H, d), 6.7(1H, d), 5.8(1H, m), 3.2(4H, m), 3.0(2H, m),2.8(2H, m), 2.7(4H, m), 2.1(3H, d), 1.9(2H, m), 1.05(3H, m).

Example 214

1-[2-(2-Pyridyl)ethyl]-4-[3-(2-cyanophenyl)-4-chloro-5-(1-fluoropropyl)]phenylpiperazine

¹H-NMR(400 MHz, CDCl₃); δ(ppm) 8.55(1H, d), 7.8(1H, d), 7.6(2H, m),7.45(2H, m), 7.2(1H, d), 7.1(2H, m), 6.8(1H, d), 5.8(1H, m), 3.25(4H,m), 3.0(3H, m), 2.8(2H, m), 2.7(4H, m), 2.0(2H, m), 1.05(3H, t).

Example 215

1-Ethyl-4-[3-(2,6-xylyl)-4-chloro-5-(1-fluoropropyl)]phenylpiperazine

¹H-NMR(400 MHz, CDCl₃); δ(ppm) 7.2-7.0(4H, m), 6.65(1H, d), 5.8(1H, m),3.2(4H, m), 2.6(4H, m), 2.5(2H, q), 2.0(6H, d), 1.9(2H, m), 1.15(3H, t),1.05(3H, t).

Example 216

1-Ethyl-4-{3-(2-trifluoromethylphenyl)-4-chloro-5-[1-(R)-fluoropropyl]}phenylpiperazine

¹H-NMR(400 MHz, CDCl₃); δ(ppm) 7.8(1H, m), 7.6(1H, m), 7.5(1H, m),7.25(1H, m), 7.05(1H, d), 6.75(1H, m), 5.8(1H, m), 3.2(4H, m), 2.6(4H,m), 2.45(2H, q), 1.9(2H, m), 1.15(3H, t), 1.05(3H, d-t).

Example 217

1-Ethyl-4-[3-(2-ethylphenyl)-4-chloro-5-(1-fluoropropyl)]phenylpiperazine

¹H-NMR(400 MHz, CDCl₃); δ(ppm) 7.4-7.2(3H, m), 7.1(1H, d), 7.05(1H, m),6.75(1H, d), 5.8(1H, m), 3.2(4H, m), 2.6(4H, m), 2.5-2.3(4H, m), 1.9(2H,m), 1.2-1.0(6H, m).

Example 218

1-(2-Hydroxyethyl)-4-[3-(2-ethylphenyl)-4-chloro-5-(1-fluoropropyl)]phenylpiperazine

¹H-NMR(400 MHz, CDCl₃); δ(ppm) 7.4-7.2 (3H, m), 7.1(1H, d), 7.05 (1H,d), 6.75(1H, d), 5.8(1H, d), 3.6(2H, t), 3.2(4H, m), 2.65(4H, m),2.60(2H, t), 2.40(2H, m), 1.9(2H, m), 1.05(6H, m).

Example 219

1-(2-Hydroxyethyl)-4-{3-(2-trifluoromethylphenyl)-4-chloro-5-[1-(R)-fluoropropyl]}phenylpiperazine

¹H-NMR(400 MHz, CDCl₃); δ(ppm) 7.8(1H, m), 7.6(1H, m), 7.5(1H, m),7.25(1H, m), 7.05(1H, d), 6.75(1H, m), 5.8(1H, m), 3.2(4H, m), 2.6(4H,m), 2.45(2H, q), 1.9(2H, m), 1.15(3H, t), 1.05(3H, d-t).

Example 220

1-Methyl-4-{3-(2-tolyl)-4-chloro-5-[1-(R)-fluoropropyl]}phenylpiperazine

¹H-NMR(400 MHz, CDCl₃); δ(ppm) 7.09-7.28(4H, m), 7.03(2H, d), 6.71(2H,d), 5.78(1H, m), 3.22(4H, m), 2.58(4H, m), 2.37(3H, s), 2.12(3H, d),1.82-2.03(2H, m), 1.07(3H, d-t).

Example 221

1-Methyl-4-{3-(2-tolyl)-4-chloro-5-[1-(S)-fluoropropyl]}phenylpiperazine

¹H-NMR(400 MHz, CDCl₃); δ(ppm) 7.09-7.28(4H, m), 7.03(2H, d), 6.71(2H,d), 5.78(1H, m), 3.22(4H, m), 2.58(4H, m), 2.37(3H, s), 2.12(3H, d),1.82-2.03(2H, m), 1.07(3H, d-t).

Example 222

1-(2-Hydroxymethyl)-4-{3-[2-(4-fluorotolyl)]-4-chloro-5-[1-(S)-fluoropropyl]}phenylpiperazine

¹H-NMR(400 MHz, CDCl₃); δ(ppm) 7.1(2H, m), 6.95(2H, m), 6.7(1H, d),5.8(1H, m), 3.7(2H, m), 3.2(4H, m), 2.7(4H, m), 2.6(2H, m), 2.1(3H, d),1.9(2H, m), 1.05(3H, m).

Example 223

1-(2-Hydroxyethyl)-4-{3-[2-(4-fluorotolyl)]-4-chloro-5-[1-(R)-fluoropropyl]}phenylpiperazine

¹H-NMR(400 MHz, CDCl₃); δ(ppm) 7.1(2H, m), 6.95(2H, m), 6.7(1H, d),5.8(1H, m), 3.7(2H, m), 3.2(4H, m), 2.7(4H, m), 2.6(2H, m), 2.1(3H, d),1.9(2H, m), 1.05(3H, m).

Example 224

Synthesis of 2-chloro-3-bromo-5-nitrobenzoic acid

26.63 g (86.3 mmol ) of ethyl 2-chloro-3-bromo-5-nitrobenzoate wasdissolved in a mixture comprising 150 ml of ethanol and 80 ml. of THF,followed by the addition of 55 ml of a 2N aqueous solution of sodiumhydroxide. The obtained mixture was stirred at room temperature for onehour, followed by the addition of water and 19 ml. of 6N hydrochloricacid. The obtained mixture was concentrated under reduced pressure andextracted with ethyl acetate. The ethyl acetate phase was washed with asaturated aqueous solution of common salt, dried and distilled to removethe solvent, giving 24.11 g of the title compound (yield: quantitative).

m.p.; 162˜163.5° C.;

¹H-NMR(400 MHz, DMSO₆); δ(ppm) 8.47(1H, d, J=2.7 Hz), 8.68(1H, d, J=2.7Hz). MS m/z: 280[M-H]⁻, 278[M-H]⁻.

Example 225

Synthesis of 2-chloro-3-bromo-5-nitrobenzoyl chloride

5.1 ml (69.9 mmol) of thionyl chloride and a solvent mixture comprising50 ml of benzene and 0.2 ml of DMF were added to 14.07 g (50.2 mmol) of2-chloro-3-bromo-5-nitrobenzoic acid. The obtained mixture was heatedunder reflux for 2 hours and distilled to remove the solvent. Benzenewas added to the residue and the obtained mixture was distilled again toremove the solvent. Thus, 15.07 g of the title compound was obtained(yield: quantitative).

This product was used in the following reaction without any additionalpurification.

¹H-NMR(400 MHz, CDCl₃); δ(ppm) 8.71(1H, d, J=2.7 Hz), 8.74(1H, d, J=2.7Hz).

Example 226

Synthesis of diethyl2-(2-chloro-3-bromo-5-nitrobenzoyl)-2-methylmalonate

2.2 g of 55% sodium hydride was suspended in 30 ml of THF, followed bythe addition of 50 ml of a THF solution of 8.65 ml (50.3 mmol) ofdiethyl methylmalonate under cooling with ice. The obtained mixture wasstirred at room temperature for 20 minutes and cooled with ice again,followed by the dropwise addition of 85 ml of a THF solution of the2-chloro-3-bromo-5-nitrobenzoyl chloride prepared in the above Example.The obtained mixture was stirred as such for 1.5 hours and then pouredinto an aqueous solution of ammonium chloride. The resulting mixture wasextracted with ethyl acetate. The ethyl acetate phase was washed with asaturated aqueous solution of sodium hydrogen carbonate and a saturatedbrine, dried and distilled to remove the solvent. 30 ml of methylenechloride was added to the residue. The resulting mixture was freed frominsolubles by filtration and concentrated under reduced pressure to give21.77 g of the title compound (yield: quantitative).

m.p.; 75˜76.5° C.; ¹H-NMR(400 MHz, CDCl₃); δ(ppm) 1.24(6H, t, J=7.1 Hz),1.84(3H, s), 4.22(2H, q, J=7.1 Hz), 4.23(2H, q, J=7.1 Hz), 8.43(1H, d,J=2.6 Hz), 8.55(1H, d, J=2.6 Hz). MS m/z: 438[MH]⁺, 436[MH]⁺.

Example 227

Synthesis of 2-chloro-3-bromo-5-nitropropiophenone

90 ml of acetic acid, 14.0 ml of concentrated hydrochloric acid and 7.0ml of concentrated sulfuric acid were added to 21.72 g of diethyl2-(2-chloro-3-bromo-5-nitrobenzoyl)-2-methylmalonate. The obtainedmixture was heated under reflux for 13 hours and then poured into amixture comprising 350 ml of ice-water and 100 ml of ethyl acetate. Theresulting mixture was extracted with ethyl acetate. The ethyl acetatephase was washed with a saturated brine and a saturated aqueous solutionof sodium hydrogen carbornate successively, dried and distilled toremove the solvent, giving 10.56 g of the title compound (yield: 72%).

m.p.; 81.5˜83° C.; ¹H-NMR(400 MHz, CDCl₃); δ(ppm) 1.25(3H, t, J=7.1 Hz),2.96(2H, q, J=7.1 Hz), 8.17(1H, d, J=2.6 Hz), 8.57(1H, d, J=2.6 Hz), MSm/z: 292[MH]⁺, 294[MH]⁺, 296[MH]⁺.

Example 228

Synthesis of 1-(2-chloro-3-bromo-5-nitrophenyl)-1-propanol

7.48 g (25.6 mmol) of 2-chloro-3-bromo-5-nitropropiophenone wasdissolved in 50 ml of methanol, followed by the addition of 735 mg (19.4mmol) of sodium borohydride under cooling with ice. The obtained mixturewas stirred for 30 minutes, followed by the addition of an aqueoussolution of ammonium chloride. The resulting mixture was extracted withethyl acetate. The ethyl acetate phase was washed with a saturatedbrine, dried and distilled to remove the solvent, giving 7.42 g of thetitle compound (yield: quantitative).

m.p.; 110˜113° C.; ¹H-NMR(400 MHz, CDCl₃); δ(ppm) 1.05(3H, t, J=7.5 Hz),1.69(1H, m), 1.88(1H, m), 2.15(1H, d, J=4.0 Hz), 5.13(1H, dt, J=7.9, 4.0Hz), 8.42(1H, d, J=2.6 Hz), 8.46(1H, d, J=2.6 Hz). MS m/z: 295[MH]³¹ ,293[M-H ]³¹ .

Example 229

Synthesis of 3-bromo-4-chloro-5-(1-fluoropropyl)-1-nitrobenzene

9.0 ml of hexafluoropropenediethylamine and 80 ml of a chloroformsolution of 7.32 g (25.0 mol) of1-(2-chloro-3-bromo-5-nitrophenyl)-1-propanol were dropwise added to 25ml of chloroform under cooling with ice in this order. The obtainedmixture was stirred as such for 40 minutes, followed by the addition ofa saturated aqueous solution of sodium hydrogen carbonate. The obtainedmixture was stirred for 30 minutes and left standing to causeliquid-liquid separation. The chloroform phase was separated. Theaqueous phase was further extractecd with ethyl acetate and the ethylacetate phase was washed with a saturated brine. The resulting ethylacetate phase and the above chloroform phase were combined, dried anddistilled to remove the solvent. The obtained residue was purified bysilica gel column chromatography to give 6.64 g of th title compound(yield: 90%).

¹H-NMR(400 MHz, CDCl₃); δ(ppm) 1.09(3H, t, J=7.5 Hz), 1.78-2.12(2H, m),5.78(1H, ddd, J=47.1, 7.9, 3.5 Hz), 8.33(1H, d, J=2.7 Hz), 8.48(1H, d,J=2.7 Hz).

Example 230

Synthesis of 3-bromo-4-chloro-5-(1-fluoropropyl)aniline

6.54 g (22.1 mmol) of 3-bromo-4-chloro-5-(1-fluoropropyl)-1-nitrobenzenewas dissolved in a solvent mixture comprising 30 ml of methanol and 90ml of acetonitrile, followed by the addition of 120 ml of a 20% solutionof titanium trichloride in diluted hydrochloric acid under a nitrogenstream under cooling with ice. The obtained mixture was stirred at roomtemperature for 3 hours and then poured into water. The resultingmixture was extratcted with ethyl acetate. The ethyl acetate phase waswashed with a saturated aqueous solution of sodium hydrogen carbonateand a saturated brine successively, dried and distilled to remove thesolvent. The residue was purified by silica gel column chromatography togive 5.04 g of the title compound (yield: 86%).

¹H-NMR(400 MHz, CDCl₃); δ(ppm) 1.03(3H, t, J=7.5 Hz), 1.7-2.1(2H, m),3.77(2H, brs), 5.66(1H, ddd, J=47.4, 7.9, 3.6 Hz), 6.74(1H, d, J=2.7Hz), 6.91(1H, d, J=2.7 Hz). MS m/z: 267[M⁺], 265[M⁺].

Example 231

Synthesis of 1-[3-bromo-4-chloro-5-(1-fluoropropyl)]phenylpeperazine

1.81 g (6.79 mmol) of 3-bromo-4-chloro-5-(1-fluoropropyl)aniline and1.28 g (7.17 mmol) of bis(2-chloroethyl)amine hydrochloride weresuspended in 6 ml of 1,2-dichlorobenzene. The obtained suspension washeated on an oil bath of 153° C. under a nitrogen stream for 11 hours,cooled, adjusted to pH8 with a 2N aqueous solution of sodium hydroxideand extracted with ethyl acetlate. The ethyl acetate phase was washedwith a saturated brine, dried and distilled to remove the solvent. Theobtained residue was purified by silica gel column chromatography togive 1.25 g (yeild: 55%) of tire title compound and 0.5 g (yield: 23%)of (E)-1-[3-bromo-4-chloro-5-(1-propenyl)]phenylpiperazine.

(E)-1-[3-bromo-4-chloro-5-(1-propenyl)]phenylpiperazine.

¹H-NMR(400 MHz, CDCl₃); δ(ppm) 1.91(3H, dd, J=6.8, 1.8 Hz), 3.66(1H,br), 6.68(1H, dq, J=15.7 Hz, 6.8 Hz), 6.72(1H, dd, J=15.7, 1.8 Hz),6.73(1H, d, J=2.7 Hz), 6.85(1H, d, J=2.7 Hz). MS m/z: 317[MH]⁺,315[MH]⁺.

Example 232

Synthesis of1-(t-butoxycarbonyl)-4-(3-bromo-4-chloro-5-carboxy)phenylpeperazine

20 ml of water, 150 ml of ethanol and 61 ml of a 2N aqueous solution ofsodium hydroxide were added to 5.2 g (13.56 mmol) of1-(3-bromo-4-chloro-5-ethoxycarbonyl)phenylpiperazinie hydrochloride,followed by the addition of a solution of 5.29 g (2 equivalents) ofdi(t-butyl) dicarbonate [Boc₂O] in 25 ml of ethanol under coolinig withice. The obtained mixture was freed from insolubles by filtration anddistilled to remove the solvent, followed by the addition of 23 min of2N hydrochloric acid under cooling with ice. The obtained mixture wasextracted with ethyl acetate. The ethyl acetate phase was dried anddistilled to remove the solvent. Isopropyl ether was added to theobtained residue to precipitate a crystal. This crystal was recovered byfiltration to give 4.64 g of the title compound (yield: 82%).

m.p.; 183˜184.5° C. (dec.); ¹H-NMR(400 MHz, CDCl₃); δ(ppm) 1.48(9H, s),3.17(4H, m), 3.58(4H, m), 4.2(1H, br), 7.30(1H, d, J=2.9 Hz), 7.36(1H,d, J=2.9 Hz). MS m/z: 420[M⁺], 418[M⁺].

Example 233

Synthesis of1-(t-butoxycarbonyl)-4-[3-bromo-4-chloro-5-(2-pyridylthio)carbonyl]phenylpiperazine

1.06 ml (13.7 mmol) of N,N-dimethylfuornanmide (hereinafter abbreviatedto “DMF”) and 0.99 ml (13.6 mmol) of thionyl chloride were added to 20ml of tetrahydrofuran (hereinafter abbreviated to “THF”), followed bystirring at room temperature for at least 30 minutes. A solution of 5 g(11.9 mmol) of1-(t-butoxycarbonyl)-4-(3-bromo-4-chloro-5-carboxy)phenylpiperazine in25 ml of THF was dropwise added to the mixture prepared above undercooling with ice, followed by stirring at 50° C. for one hour. Asolution of 2.07 g (18.6 mmol) of 2-mercaptopyridine and 5.2 ml (37.3mmol) of triethylamine in 30 ml of THF was with ice. The obtainedmixture was stirred at room temperature for about one hour and thenpoured into ice-water. The resulting mixture was extracted with ethylacetate. The organic phase was washed with a 1N aqueous solution ofsodium hydroxide and a saturated brine, dried and distilled to removethe solvent. Isopropyl ether was added to the residue to precipitate acrystal. This crystal was recovered by filtration to give 5.61 g of thetitle compound (yield: 92%).

Example 234

Synthesis of1-(t-butoxycarbonyl)-4-[3-bromo-4-chloro-5-(2-pyridylthio)carbonyl]phenylpiperazine

5 g (11.9 mmol) of1-(t-Butoxycarbonyl)-4-(3-bromo-4-chloro-5-carboxy)phenylpiperazine and3.5 ml (25.1 mmol) of triethylamine were dissolved in 20 ml of THF. 30ml of a solution of 2.7 ml (13.0 mmol) of diphenylphosphoric chloride inTHF was dropwise added to the solution prepared above under cooling withice, followed by stirring at room temperature for one hour. A solutionof 1.51 g (1.14 equivalents) of 2-mercaptopyriditine in 30 ml of THF wasdropwise added to the resulting mixture under cooling with ice. Theobtained mixture was stirred at 50° C. for one hour and then poured intoice-water. The resulting mixture was extracted with ethyl acetate. Theorganic phase was washed with a 1N aqucois solution of sodium hydroxideand a saturated brine, dried and distilled to remove the solvent.Isopropyl ether was added to the residue to precipitate a crystal. Thiscrystal was recovered by filtration to give 5.93 g of the title compound(yield: 97%).

m.p.; 156˜157° C.; ¹H-NMR(400 MHz, CDCl₃); δ(ppm) 1.48(9H, s), 3.19(4H,m), 3.58(4H, m), 7.15(1H, d, J=2.9 Hz), 7.24(1H, d, J=2.9 Hz), 7.35(1H,ddd, J=7.3, 4.8, 1.5 Hz), 7.77(1H, ddd, J=7.9, 1.5, 0.9 Hz), 7.82(1H,ddd, J=7.9, 7.3, 1.8 Hz), 8.67(1H, ddd, J=4.8, 1.8, 0.9 Hz). MS m/z:514[MH]⁺, 512[MH]⁺.

Example 235

Synthesis of1-(t-butoxycarbonyl)-4-(3-bromo-4-chloro-5-propionyl)phenylpiperazine

4.5 g (8.78 mnmol) of1-(t-butoxycarbonnyl)-4-[3-bromo-4-chloro-5-(2-pyridylthio)carbonyl]phenylpiperazinewas dissolved in 50 ml of THF. 9.7 ml of a 1M solution of ethylmagnesiumbromidie in THF was dropwise added to the obtained solution in 30minutes, followed by the addition of a saturated aqueous solution ofammonium chloride and water in this order. The resulting mixture wasextracted with ethyl acetate. The organic phase was washed with a 1Naqueous solution of sodium hydroxide and a saturated brine, dried anddistilled to remove the solvent. The residue was purified by silica gelcolumn chromatography (with ethyl acetate/hexane) to give 2.28 g of thetitle compound (yield: 60%).

m.p.; 119˜122.5° C.; ¹H-NMR(400 MHz, CDCl₃); δ(ppm) 1.20(3H, t, J=7.3Hz), 1.48(9H, s), 2.91(2H, q, J=7.3 Hz), 3.15(4H, m), 3.57(4H, m),6.72(1H, d, J=2.9 Hz), 7.19(1H, d, J=2.9 Hz). MS m/z: 432[M⁺], 430[M⁺].

Example 236

Synthesis of 1-(3,5-dibromo-4-chloro)-phenylpiperazine

10.0 g (35 mmol) 3,5-dibromo-4-chloroaniline (CAS registration No.35754-04-2) and 15.6 g (87.5 mmol ) of bis(2-chloroethyl)aminehydrochloride were suspended in 120 ml of 1,2-dichlorobenzene. Theobtained suspension was heated on an oil bath of 180° C. under anitrogen stream for 8 hours. 300 ml of ethyl acetate was added to theresulting mixture to form a precipitate. This precipitate was recoveredby filtration, washed with ethyl acetate and suspended in 500 ml ofmethanol. The obtained suspension was heated under reflux, freed frominsolubles by filtration, and distilled to remove the solvent. Thecrystal thus precipitated was recovered by filtration to give 13.7 g ofthe title compound (yield: 100%).

m.p.; over 270° C.;

¹H-NMR(400 MHz, DMSO-d₆); δ(ppm) 3.14(4H, m), 3.46(4H, m), 7.38(2H, s).MS m/z: 357[MH]⁺, 355[MH]⁺, 353[MH]⁺.

Example 237

Synthesis of1-(t-butoxycarbonyl)-4-(3,5-dibromo-4-chloro)phenylpiperazine

13.7 g (35 mmol) of 1-(3,5-dibromo-4-chloro)phenylpiperazine wassuspended in 200 ml of acetonitrile, followed by the dropwise additionof 14.4 ml (70 mmol) of triethlylamine under cooling with ice. Asolution of 11.1 g (42 mmol) of di(t-butyl) dicarbonate in 15 ml ofacetonitrile was dropwise added to the resulting mixture under coolingwith ice in 10 minutes. The obtained mixture was stirred at roomtemperature for 15 hours, followed by the addition of water. Theresulting mixture was extracted with ethyl acetate. The organic phasewas washed with water, dried and concentrated under reduced pressure.The obtained residue was purified by silica gel chromatography (withethyl ether/hexane) to give 17.8 g of the title compound as a colorlesscrystal (yield: 83.3%).

m.p.; 149˜151° C.; ¹H-NMR(400 MHz, CDCl₃); δ(ppm) 1.48(9H, s), 3.13(4H,m), 3.57(4H, m), 7.10(2H, s). MS m/z: 456[M]⁺, 454[M]⁺, 452[M]⁺.

Example 238

Synthesis of1-(t-butoxycarbonyl)-4-(3-bromo-4-chloro-5-propionyl)-phenylpiperazine

3.8 ml of a 1.66M solution of n-butyllithium in n-hexane was dropwiseadded to a solution of 2.5 g (5.5 mmol) of1-(t-butoxycarbonyl)-4-(3,5-dibromo-4-chloro)phenylpiperazine in 10 mlof THF in about 5 minutes at −100° C. Then, a solution of 860 mg (6.6mmol) of propionic anhydride in 2.5 ml of THF was dropwise added to theabove-prepared mixture at −100° C. in about 3 minutes. The obtainedmixture was stirred as such for one hour (during this stirring, thetemperature rose from −100° C. to −20° C.). A saturated aqueous solutionof ammonium chloride was added to the resulting mixture, followed byextraction with ethyl acetate. The organic phase was washed with waterand a saturated brine, dried and distilled to remove the solvent. Theresidue was purified by silica gel column chromatography (with ethylacetate/n-hexane) to give 1.55 g of the title compound (yield: 65%).

15 ml of isopropanol was added to the above product. The product wasdissolved in the isopropanol by heating and the obtained solution wasstirred under cooling with ice for one hour to precipitate a crystal.This crystal was recovered by filtration to give 1.0 g of the titlecompound as a crystal (yield: 42.1%).

m.p.: 121˜123° C.; ¹H-NMR(400 MHz, CDCl₃); δ(ppm) 1.20(3H, t, J=7.3 Hz),1.48(9H, s), 2.91(2H, q, J=7.3 Hz), 3.15(4H, m), 3.57(4H, m), 6.72(1H,d, J=2.9 Hz), 7.19(1H, d, J=2.9 Hz).

Example 239

Synthesis of1-(t-butoxycarbonyl)-4-(3-bromo-4-chloro-5-hydroxypropyl)phenylpiperazine

0.8 ml (1.2 equivalents) of a 1.66 M solution of n-butyllithium inn-hexane was dropwise added to a solution of 500 g (1.1 mmol) of1-(t-butoxycarbonyl)-4-(3,5-dibromo-4-chloro)phenylpiperazine in 10 mlof THF at −76° C. in about 4 minutes, followed by the dropwise additionof a solution of 77 mg (1.3 mmol) of propionaldehyde in 0.5 ml of THF at−76° C. in about 2 minutes. The obtained mixture was stirred as such forone hour (during this stirring, the temperature rose from −76° C. to−10° C.). A saturated aqueous solution of ammonium chloride was added tothe resulting mixture, followed by extraction with ethyl acetate. Theorganic phase was washed with water and a saturated brine, dried anddistilled to remove the solvent. The residue was purified by silica gelcolumn chromatography (with ethyl acetate/n-hexane) to give 0.31 g ofthe title compound as a colorless oil (yield: 65%).

¹H-NMR(400 MHz, DMSO-d₆); δ(ppm) 1.01(3H, t, J=7.6 Hz), 1.48(9H, s),1.6-1.9(2H, m), 3.15(4H, m), 3.58(4H, m), 5.03(1H, m), 6.07(1H, d, J=2.9Hz), 7.10(1H, d, J=2.9 Hz). MS m/z: 434[M]⁺, 432[M]⁺.

Example 240

Synthesis of1-(2-trimethylsilyloxyethyl)-4-[3-bromo-4-chloro-5-(1-fluoropropyl)]phenylpiperazine

500 mg (1.05 mmol) of1-(2-hydroxyethyl)-4-[3-bromo-4-chloro-5-(1-fluoropropyl)]phenylpiperazinemethanesulfonate was suspended in 5 ml of ethyl acetate, followed by theaddition of 0.35 ml (2.50 mmol) of triethylamine under cooling with ice.A solution of 0.16 ml (1.26 mmol) of trimethylsilyl chloride in 1 ml ofethyl acetate was dropwise added to the resulting mixture while stirringthe mixture under cooling with ice. The obtained mixture was stirred atroom temperature for 1.5 hours, followed by the addition of 5 ml ofn-hexane. The obtained mixture was filtered to remove insolubles and thefiltrate was concentrated under reduced pressure to give 0.51 g of thetitle compound. This product was used in the following reaction withoutany additional purification.

¹H-NMR(400 MHz, CDCl₃); δ(ppm) 0.13(9H, s), 1.04(3H, t, J=7.3 Hz),1.7-2.0(2H, m), 2.58(2H, t, J=6.2 Hz), 2.66(4H, m), 3.19(4H, m),3.75(2H, J=6.2 Hz), 5.69(1H, ddd, J=47.5, 7.9, 3.7 Hz), 6.95(1H, d,J=2.9 Hz), 7.09(1H, d, J=2.9 Hz).

Example 241

Synthesis of1-(2-hydroxyethyl)-4-[3-(2-cyanophenyl-4-chloro-5-(1-fluoropropyl)]phenylpiperazine

1-(2-Trimethylsilyloxyethyl)-4-[3-bromo-4-chloro-5-(1-fluoropropyl)]phenylpiperazinewas dissolved in 4 ml of DMF, followed by the addition of 334 mg (1.58mmol) of potassium phosphate and 61 mg (0.05 mmol) oftetrakis(triphenylphosphine)palladium (0). A solution of 236 mg (1.26mmol ) of 2-(1,3,2-dioxaborinan-2-yl)benzonitrile in 3 ml of DMF wasdropwise added to the resulting mixture at 100° C. in 30 minutes. Theobtained mixture was stirred as such at 100° C. for 30 minutes andcooled, followed by the addition of water. The resulting mixture wasextracted with ethyl acetate. The organic phase was washed with waterand a saturated brine, dried and distilled to remove the solvent, giving0.52 g of a residue.

This residue was dissolved in 1 ml of ethanol, followed by the dropwiseaddition of 0.57 g of a 10% solution of hydrochloric acid in ethanolunder cooling with ice. The obtained mixture was stirred at 4° C. for 20hours to give a precipitate. The precipitate was recovered by filtrationand dried to give 0.39 g of the title compound (yield: 83.9%).

Example 242

Synthesis of1-(t-butoxycarbonyl)-4-{3-bromo-4-chloro-5-[1-(S)-hydroxypropyl)]}phenylpiperazine

55.8 g (173 mmol) of (−)-Dip-chloride [CAS registration No. 85116-37-6]was added to a solution of 30.0 g (69.7 mmol) of1-(t-butoxycarbonyl)-4-(3-bromo-4-chloro-5-propionyl)phenylpiperazine in450 ml of THF. The obtained mixture was stirred at room temperature for24 hours. Water and ethyl acetate were added to the reaction mixture toconduct partition. The organic phase was washed with water and a brine,dried and distilled to remove the solvent. The residue was purified bysilica gel chromatography to give 27.2 g of the title compound (yield:90%, optical purity; 94%ee).

<Method for the determination of optical purity>

A proper amount of a sample was deprotected with trifluoroacetic acidand treated with carbobenzoxy chloride (hereinafter abbreviated to“Z-Cl”) to form an N-Z derivative, which was used as a test sample.

<Conditions of determination>

stationary phase: CHIRALPAK AD (a product of Daicel Chemical IndustriesLtd.)

Φ 4.6×250 mm

mobile phase: ethanol (0.5 ml/min.)

detector: UV detector, at 254 nm

<Retention time> S isomer: 23 to 24 min.

R isomer: 28 to 30 min.

Example 243

Synthesios of1-(t-butoxycarbonyl)-4-{3-bromo-4-chloro-5-[1-(R)-fluoropronyl]}phenylpiperazine

19.4 g (41.5 mmol) of hexafluoropropenediethylamine was dropwise addedto a solution of 18.0 g (41.5 mmol, 94%ee) of1-(t-butoxycarbonyl)-4-{3-bromo-4-chloro-5-[1-(S)-hydroxypropyl]}phenylpiperazinein 90 ml of chloroform under cooling with ice. The obtained mixture wasstirred as such for 2 hours. 90 ml of carbon tetrachloride was added tothe reaction mixture to precipitate a salt, which was filtered out. 80ml of water was added to the filtrate to conduct partition. The organicphase was washed with a brine and distilled to remove the solvent. Theobtained residue was purified by silica gel chromatography to give 11.2g of the title compound (yield: 62%, optical purity: 55%ee).

<Method for the determination of optical purity>

The optical purity was determined under the same conditions as thosedescribed above.

<Retention time> S isomer: 17 to 19 min.

R isomer: 20 to 21 min.

Example 244

Synthesis of1-(t-butoxycarbonyl)-4-{3-bromo-4-chloro-5-[1-(R)-fluoropropyl]}phenylpiperazine

A solution of 15.0 g (34.6 mmol) of1-(t-butoxycarbonyl)-4-{3-bromo-4-chloro-5-[1-(s)-hydroxypropyl]}phenylpiperazinein 30 ml of methylene chloride was dropwise added to a solution of 6.15g (38.0 mmol) of diethylaminosulfur trifluoride in 1.5 ml of methylenechloride at −70° C. The resulting mixture was stirred as such for onehour, brought to room temperature and neutralized with a saturatedaqueous solution of sodium hydrogen carbonate. The resulting mixture wasextracted within methylene chloride. The organic phase was washed withwater and distilled to remove the solvent. The residue was purified bysilica gel chromatography to give 12.5 g of the title compound (yield:83%, optical purity: 34%ee).

<Method for the determination of optical purity>

The optical purity was determined under the same conditions as thosedescribed above.

Example 245

Synthesis of 1-{3-bromo-4-chloro-5-[1-(R)-fluoropropyl]}phenylpiperazine

A solution of 6.75 g (68.8 mmol) of concentrated sulfuric acid in 25 mlof ethanol was added to a solution of 15.0 g (34.4 mmol) of1-(t-butoxycarbonyl)-4-{3-bromo-4-chloro-5-[1-(R)-fluoropropyl]}phenylpiperaziniein 50 ml of ethanol. The obtained mixture was stirred at 50° C. for 3hours and then concentrated under reduced pressure. Ethyl acetate and a5N aqueous solution of sodium hydroxide were added to the obtainedresidue to conduct partition. The organic phase was washed with a brineand distilled to remove the solvent, giving 10.3 g of the title compound(yield: 89%).

<Method for the determination of optical purity>

The optical purity was determined under the same conditions as thosedescribed above.

<Retention time> S isomer: 17 to 19 min.

R isomer: 20 to 21 min.

Example 246

Synthesis of1-{3-(2-cyanophenyl)-4-chloro-5-[1-(R)-fluoropropyl]}phenylpiperazine

14.0 g (41.7 mmol) of1-{3-bromo-4-chloro-5-[1-(R)-fluoropropyl]}phenylpiperazine, 2.4 g (2.08mmol) of tetrakis(triphenylphosphine)palladium and 13.3 g (62.6 mmol) ofanhydrous tripotassium phosphate were suspended in 28 ml of DMF,followed by the dropwise addition of a solution of 9.5 g (50.0 mmol) of2-(1,3,2-dioxaborinan-2-yl)benzonitrile in 19 ml of DMF at 100° C. Theobtained mixture was stirred as such for 3 hours and then cooled to roomtemperature. Water and ethyl acetate were added to the resulting mixtureto conduct partition. The organic phase was washed with a brine anddistilled to remove the solvent. The obtained residue was purified bysilica gel chromatography to give 10.6 g of the title compound (yield:71%).

<Method for the determination of optical purity>

The optical purity was determined under the same conditions as thosedescribed above.

<Retention time> S isomer: 10 to 12 min.

R isomer: 12 to 14 min.

Example 247

Optical purification of1-{3-(2-cyanophenyl)-4-chloro-5-[1-(R)-fluoropropyl]}phenylpiperazine

A solution of 4.0 g (10.5 mmol) of (+)-di-p-toluoyl-D-tartaric acid in100 ml of methanol was added to a solution of 10.0 g (27.9 mmol, 55%ee)of the title compound prepared in the above Example in 300 ml ofmethanol at room temperature. After then precipitation of a crystal, theresulting mixture was stirred under cooling with ice for one hour andthe filtered to recover the crystal. The crystal was neutralized with a5N aqueous solution of sodium hydroxide and the resulting mixture wasextracted with ethyl acetate. The organic phase was washed with a brineand distilled to remove the solvent, giving 6.4 g of the title compoundas an optically active substance (yield: 64%, optical purity: 90%ee).

<Method for the determination of optical purity>

The optical purity was determined under the same conditions as thosedescribed above.

Example 248

Synthesis of1-(2-hydroxyethyl)-4-{3-(2-cyanophenyl)-4-chloro-5-[1-(R)-fluoropropyl]}phenylpiperazinehydrochloride

2.8 g (28.0 mmol) of triethylamine and 3.5 g (28.0 mmol) of2-bromoethanol were added to a solution of 5.0 g (14.0 mmol) of theoptically active1-{3-(2-cyanophenyl)-4-chloro-5-[1-(R)-fluoropropyl]}phenylpiperazineprepared in the above Example in 10 ml of DMF. The obtained mixture wasstirred at 50° C. for 3 hours and then cooled to room temperature. Waterand toluene were added to the resulting mixture to conduct partition.The organic phase was washed with water and distilled to remove thesolvent, giving 5.5 g of the title compound as a crude product (yield:98%).

A solution of 5.5 g (13.7 mmol) of this crude product in 55 ml of 3%methanol/ethanol was dropwise added to a solution of 1.52 g (15.1 mmol)of concentrated hydrochloric acid in 27.5 ml of ethanol at 60° C. Afterthe completion of the dropwise addition, the resulting mixture wasstirred while cooled by allowing to stand. After the precipitation of acrystal, the resulting mixture was further stirred under cooling withice for one hour and filtered to recover the crystal. Thus, 5.2 g of thetitle compound (i.e., a hydrochloride) was obtained (yield: 86%).

The compounds of the present invention were subjected to each ofserotonin S₂ receptor binding test, dopamine D₂ receptor binding testand adrenergic α₁ receptor binding test. The methods and results, whichexhibit the effect of the present invention, will be given hereinafter.

<Method>

1. Reagent

The following reagents were used in this test.

(1) Methylsergide maleate (a product of RBI)

(2) Spiperone (a product of Sigma)

(3) Phentolamine (a product of Sigma)

Further, the following reagents (all of which products of NEN) were usedas radioisotope-labeled compounds.

(4) Ketanserin hydrochloride [ethylene-³H]

(5) Spiperone [benzene ring-³H]

(6) Prazosin [7-methoxy-³H]

These reagents and samples were each dissolved in 10% ethanol beforeuse. Among them, water-insoluble compounds were each dissolved inethanol and the obtained solution was diluted with distilled water to anethanol concentration of 10%. Further, Methylsergide maleate was used ina state dissolved in distilled water.

2. Animal

SD rats aged 6 to 8 weeks were used.

3. Preparation of Receptor Sources

SD rats were each slaughtered with a guillotine to extirpate itscerebrum. The cortex and corpus striatum were separated from thecerebrum. The former was used in serotonin S₂ receptor binding test andadrenergic α₁, receptor binding test, while the latter was used indopamine D₂ receptor binding test.

The cortex was homogenized in a 0.32 M sucrose solution in an amount tentimes the wet weight of the cortex by the use of a teflon glasshomogenizer and the resulting mixture was centrifuged at 10,000×G for 20minutes. The obtained sediment was suspended in 50 mM Tris hydrochloride(pH 7.4) in an amount ten times the initial wet weight of the cortex bythe use of a histocothrom, and the obtained suspension was centrifugedat 10,000×G for 20 minutes. This operation was repeated twice. Theobtained sediment was suspended in 50 mM Tris hydrochloride (pH 7.4) inan amount 20 times the initial wet weight of the cortex by the use of ahistocothrom. The suspension thus prepared was used as a receptorfraction. This receptor fraction was stored at −80° C. until use.

On the other hand, the corpus striatum was homogenized in a 0.32 Msucrose solution in an amount ten times the wet weight of the corpusstriatum by the use of a teflon glass homogenizer and the obtainedmixture was centrifuged at 1,000×G for 20 minutes. The obtainedsupernatant was centrifuged at 10,000×G for 20 minutes. The obtainedsediments were suspended together in 50 mM Tris hydrochloride (pH 7.4)in an amount ten times the initial wet weight of the corpus striatum bythe use of a histocothrom, and the obtained suspension was centrifugedat 10,000×G for 20 minutes. This operation was repeated thrice. Theresulting sediment was suspended in 50 mM Krebs-Tris (pH 7.4) in anamount 100 times the initial wet weight of the corpus striatum by theuse of a histocothrom. The obtained suspension was used as a receptorfraction. This receptor fraction was stored at −80° C. until use.

4. [³] Ketanserin Binding Test

The receptor fraction prepared from the cortex was molten and suspendedby the use of a histocothrom. The resulting suspension was incubatedtogether with 1 nM-[³H] Ketanserin at 37° C. for 15 minutes. Theresulting reaction system was filtered through a Whatman GF/B glassfilter with an MR-30R type cell harvester mfd. by Blandel. The resultingfilter was washed twice with 5 ml of 50 mM Tris hydrochloride (ph 7.4)cooled with ice and the radioactivity of the Ketanserin bound thereceptor was determined by the use of a liquid scintillation counterwith 5 ml of ACS II. The binding detected in the presence of 1 μl ofMethylsergide was regarded as nonspecific binding.

Each IC₅₀ value was calculated by the probit method and each Ki valuewas determined by the following formula:${Ki} = {\frac{{IC}_{50}}{1 + {C/{Kd}}}.}$

In the above formula, C represents the concentration of radioligand, andKd represents the affinity of radioligand for the receptor as determinedby the Scatchard analysis.

5. [³H] Spiperone Binding Test

This test was conducted in the same manner as that of the binding testof [³H] Ketanserin except that the receptor fraction prepared from thecorpus striatum was molten and suspended with a histocothrom, and theobtained suspension was incubated together with 1 nM-[³H], Spiperone atroom temperature for 60 minutes and that the binding detected in thepresence of 10 μl of Spiperone was regarded as nonspecific binding.

6. [³H] Prazosin Binding Test

This test was conducted in the same manner as that of the binding testof [³H] Ketanserin except that the receptor fraction prepared from thecortex was molten and suspended with a histocothrom, and the obtainedsuspension was incubated together with 1 nM-[³H] Prazosin at roomtemperature for 60 minutes and that the binding detected in the presenceof 10 μl of Phentolamine was regarded as nonspecific binding.

<Result>

The results of the evaluation of compounds according to the presentinvention are given in Tables 1 to 8.

TABLE 1 Ki value (nM) serotonin S₂ dopamine D₂ adrenergic Ex. receptorreceptor αhd 1 receptor 13 24.9 4.05 404 17 374 >100 550 18 6.15 0.7553.7 19 1.95 0.64 81.6 20 6.11 2.82 313.6 21 14.4 1.85 418 22 19.2 2.84809 23 51.2 7.22 — 24 40.9 3.60 537 25 8.27 2.40 >1000 26 21.62.67 >1000 27 10.9 11.2 455 28 5.67 1.60 50.8 29 4.86 1.19 50.1 30 2.240.86 92.5 31 12.4 0.69 36.1 32 3.36 0.38 19.5 33 6.46 2.02 86.9 34 7.770.37 25.8 35 3.37 0.50 17.0 36 4.04 1.26 25.3 40 3.64 9.25 >1000

TABLE 2 Ki value (nM) serotonin S₂ dopamine D₂ adrenergic Ex. receptorreceptor αhd 1 receptor 45 192 26.9 183 46 2.16 9.78 >1000 47 5.7212.9 >1000 48 4.32 25.8 >1000 49 20.1 6.09 >1000 50 17.7 9.14 >1000 51164 27.2 >1000 52 21.6 0.99 >1000 53 12.4 6.73 >1000 54 37.5 6.06 >100055 113.04 3.10 >1000

TABLE 3 Ki value (nM) serotonin S₂ dopamine D₂ adrenergic Ex. receptorreceptor αhd 1 receptor 56 212 111 503 57 >1000 >1000 >100058 >1000 >1000 290 59 36.7 47.0 301 60 >1000 >1000 >100061 >1000 >1000 >1000 62 >1000 >1000 >1000 63 703 >1000 >1000 64 284 384459 65 26.6 6.60 79.0 66 65.9 18.3 127 67 >1000 >1000 687 68 32.0 35.1195 69 67.1 171 321 70 128 41.9 322 71 90.9 14.7 131 72 108 50.3 270 73635 577 332 74 374 >1000 >1000 75 486 >1000 >1000 76 145 50.1 112 7724.3 40.0 182 78 33.2 4.22 74.8 79 192 28.5 69.8 80 177 810 >1000

TABLE 4 Ki value (nM) serotonin S₂ dopamine D₂ adrenergic Ex. receptorreceptor αhd 1 receptor 81 241 38.3 >1000 82 10.7 39.1 723 83 84.5485 >1000 84 66.2 44.6 >1000 85 >1000 >1000 >1000 86 29.4 10.5 >1000 87283 135 >1000 88 8.33 7.35 493 89 310 44.6 >1000 90 685 263 >1000 9137.1 7.34 323 92 1.14 2.71 942 93 1.31 28.0 719 94 109 13.8 600 95 40.9104 279 96 35.3 1.33 >1000 97 247 >1000 >1000 98 19.3 64.5 >1000 99 1702.93 >1000 100 827 82.7 846 101 262 118 >1000 102 >1000 >1000 525 1036.65 101 >1000 104 24.5 70.1 >1000 105 5.21 30.2 620 106 380 44.0 >1000107 >1000 429 >1000 108 4.00 162 408 109 230 >1000 >1000 110 >1000 >1000>1000

TABLE 5 Ki value (nM) serotonin S₂ dopamine D₂ adrenergic Ex. receptorreceptor αhd 1 receptor 111 58.0 41.9 210 112 7.00 972 >1000 113 21.18.73 28.9 114 151 165 569 115 212 81.4 >1000 116 39.5 9.65 >1000 117 14849.6 334 118 468 149 >1000 119 34.9 35.8 >1000 120 17.4 0.36 77.6 121168 11.0 308 122 123 45.9 68.1 123 17.9 27.0 >1000 124 >1000 99.2 >1000125 1.49 101 >1000 126 27.3 54.6 >1000 127 11.4 1.04 65.9 128 1.1646.1 >1000 129 34.9 1.86 39.8 130 58.0 29.7 70.4 131 20.8 3.30 >1000 132392 281 >1000 133 9.02 28.7 >1000 134 30.3 59.7 >1000 135 16.042.1 >1000 136 89.0 14.2 472 137 144 0.64 312 138 25.0 2.89 9.33 1395.38 2.34 68.7 140 26.2 2.97 95.5

TABLE 6 Ki value (nM) serotonin S₂ dopamine D₂ adrenergic Ex. receptorreceptor αhd 1 receptor 141 92.7 24.9 >1000 142 20.5 1.77 653 143 15616.9 >1000 144 15.7 0.81 67.4 145 72.5 8.28 >1000 146 13.2 0.83 349 14715.1 0.45 33.2 148 22.4 12.1 278 149 11.6 6.24 27.2 150 97.1 7.98 >1000151 27.7 3.52 >1000 153 4.19 1.53 68.7 154 153 2.59 >1000 155 179.6 41.0845.0 156 29.0 1.39 513.4 157 74.4 7.26 >1000 158 124 12.4 >1000 1598.81 3.93 596 160 14.8 13.6 >1000 161 22.5 9.80 776 162 6.15 0.75 53.7163 63.6 10.2 195 164 12.0 1.62 >1000 165 6.10 0.74 >1000 166 5.421.42 >1000 167 23.8 45.4 >1000 168 180 31.9 >1000 169 108 41.8 >1000 1702.77 34.2 >1000

TABLE 7 Ki value (nM) serotonin S₂ dopamine D₂ adrenergic Ex. receptorreceptor αhd 1 receptor 171 2.74 86.7 >1000 172 30.3 48.9 >1000173 >1000 19.2 >1000 174 48.7 31.8 >1000 175 >100 29.32 >1000 176178 >100 >1000 177 >100 >100 >1000 178 12.2 7.30 >1000 179 6.54 6.0872.7 180 3.48 13.0 >100 181 0.50 26.2 >100 182 145 2.34 186 183 81.2165 >1000 184 2.09 0.17 4.52 185 >100 0.58 >1000 186 4.29 2.96 >1000 18738.2 0.54 7.80 188 47.8 1.33 19.0 189 >100 1.51 32.5 190 18.5 40.4 >1000191 3.76 1.65 21.2 192 374 >100 550 193 1.61 19.3 585 194 4.450.83 >1000 195 5.75 70.6 >1000 196 13.2 5.52 744 197 8.86 1.40 31.4 1981.06 12.1 62.7 199 63.2 51.5 — 200 — — —

TABLE 8 Ki value (nM) serotonin S₂ dopamine D₂ adrenergic Ex. receptorreceptor αhd 1 receptor 201 3.17 19.7 12.9 202 6.33 90.5 — 203 54.8 — —204 187 14.4 — 205 51.2 2.83 — 206 4.29 1.06 47.8 207 81.1 240.3 >1000208 16.1 3.46 2379 209 42.7 3.90 — 210 6.25 16.1 — 211 8.81 4.14 1024212 1019 3.90 — 213 10.3 14.3 236 214 3.78 5.15 51.7 215 15.3 2.28 — 21679.0 11.3 — 217 25.5 3.57 — 218 30.1 5.39 — 219 151 5.54 — 220 37.9 1.251680 221 4.53 3.45 486 222 12.0 6.50 1040 223 1860 6.61 1510 risperidone0.62 5.03 2.94

It can be understood from the results of the Tables 1 to 8 that thebiphenyl derivative of the present invention exhibits excellenttherapeutic and ameliorative effects on mental disorders such ascerebrovascular disorder, aggressive behavior due to senile dementia,mental excitation, poriomania, delirium, hallucination, hyperkinesia,schizophrenia, emotional disturbance, depression, neurosis,psychophysiologic disorder and anxiety neurosis.

The invention being thus described, it will be obvious that the same maybe varied in many ways. Such variations are not to be regarded as adeparture from the spirit and scope of the invention, and all, suchmodifications as would be obvious to one skilled in the art are intendedto be included within the scope of the following claims.

What we claim is:
 1. A biphenyl compound represented by the followingformula (I) or a pharmacologically acceptable salt thereof:

wherein R¹ represents a hydroxyl group, an amino group, a cyano group, apyrrolidyl group, a cyano lower alkyl group, a hydroxy lower alkylgroup, a lower alkoxyalkyl group, a halogenated heteroarylalkyl groupselected from the group consisting of a furfuryl group, and apyridylmethyl group, wherein a halogen is attached to the heteroarylring, a lower acylalkyl group, a heteroarylalkoxyalkyl group selectedfrom the group consisting of a furfuryl group, and a pyridylmethyl groupto which the oxyalkyl is bonded, an aralkyloxyalkyl group selected fromthe group consisting of a benzyl group, a methylbenzyl group, aphenethyl group and a phenylpropyl group to which the oxyalkyl isbonded, an alkenyloxyalkyl group, a lower alkoxycarbonylalkyl group, alower alkoxyalkoxyalkyl group, an arylhydroxyalkyl group selected fromthe group consisting of a benzyl group, a methylbenzyl group, aphenethyl group and a phenylpropyl group to which the hydroxyalkyl isbonded, a hydroxyheteroarylalkyl group selected from the groupconsisting of a furfuryl group, and a pyridylmethyl group, to which thehydroxyalkyl is bonded, a cycloalkylalkoxyalkyl group, alkenyl group, ahalogenated alkenyl group, a halogenated aralkyl group selected from thegroup consisting of a benzyl group, methylbenzyl group, a phenethylgroup and a phenylpropyl group, wherein a halogen is attached to thearyl ring, a halogenated hydroxyiminoaralkyl group wherein the aralkylgroup is selected from the group consisting of a benzyl group, amethylbenzyl group, a phenethyl group and a phenylpropyl group, whereina halogen is attached to the aryl ring, a lower alkoxy group loweralkoxyalkoxy group, an aryl group selected from the group consisting ofa phenyl group, a tolyl group, a xylyl group, a methoxyphenyl group, achlorophenyl group, a bromophenyl group, a fluorophenyl group, anitrophenyl group and a cyanophenyl group, a heteroaryl group selectedfrom the group consisting a furanyl group, a pyranyl group, and apyridyl group, a formyl group, a lower acyl group, a pyridylacetyl andpyridylcarbonyl groups, an aralkylcarbonyl group selected from the groupconsisting of a benzyl group, a methylbenzyl group, a phenethyl groupand a phenylpropyl group to which a carbonyl group is bonded, acycloalkylalkylcarbonyl group, a heoeroarylalkylcarbonyl group, selectedfrom the group consisting of a furfuryl group, and a pyridylmethylgroup, to which a carbonyl group is bonded, a halogenatedaralkylcarbonyl group selected from the group consisting of a benzylgroup, a methylbenzyl group, a phenethyl group and a phenylpropyl groupto which a carbonyl group is bonded and wherein a halogen is attached tothe aryl ring, a lower alkoxycarbonyl group, a lower alkylamino group, ahalogenated lower alkylsulfonylamino group, an arylsulfonylamino groupselected from the group consisting of a phenyl group, a tolyl group, axylyl group, a methoxyphenyl group, a chlorophenyl group, a bromophenylgroup, a fluorophenyl group, nitrophenyl group and a cyanophenyl groupto which a sulfonylamino group is bonded, a halogenatedarylsulfonylamino group selected from the group consisting of a phenylgroup, a tolyl group, a xylyl group, a methoxyphenyl group, achlorophenyl group, a bromophenyl group, a fluorophenyl group, anitrophenyl group and a cyanophenyl group to which a sulfonylamino groupis bonded and wherein a halogen atom is bonded to the aryl ring, atetrahydrofuranyl or tetrahydropyranyl group, a lower cyclic acetalgroup, a lower cyclic thioacetal group, a lower alkylsulfinyl group, alower alkylsulfonyl group, an aminosulfonyl group, a loweralkylaminosulfonyl group, an arylaminosulfonyl group selected from thegroup consisting of a phenyl group, a tolyl group, a xylyl group, amethoxyphenyl group, a chlorophenyl group, a bromophenyl group, afluorophenyl group, a nitrophenyl group and a cyanophenyl group to whichan aminosulfonyl group is bonded, a cycloalkylaminosulfonyl group, ahalogenated lower alkylsulfonyl group, a halogenated aryloxy loweralkylsulfonyl group selected from the group consisting of a phenylgroup, a tolyl group, a xylyl group, a methoxyphenyl group, achlorophenyl group, a bromophenyl group, a fluorophenyl group, anitrophenyl group and a cyanophenyl group bonded to anoxyloweralkylsulfonyl group and wherein a halogen atom is attached tothe aryl ring or R¹ is a cyano lower alkylsulfonyl group; R² representsa hydrogen atom, a halogen atom, a cyano group, a hydroxyl group or alower alkoxy group; R³ represents a hydrogen atom, a halogen atom, acyano group, a lower alkyl group, a halogenated lower alkyl group, alower alkoxyalkyl group or a lower alkoxy group; R⁴ represents ahydrogen atom, a halogen atom, a hydroxy lower alkyl group, ahydroxyiminomethyl group or a formyl group; R⁵ represents a halogenatedlower alkyl group, a hydroxy lower alkyl group or a lower alkoxycarbonylgroup or an aryloxycarbonyl group selected from the group consisting ofa phenyl group, a tolyl group, a xylyl group, a methoxyphenyl group, achlorophenyl group, a bromophenyl group, a fluorophenyl group, anitrophenyl group and a cyanophenyl group to which the oxycarbonyl groupis bonded; and n is
 0. 2. The biphenyl compound or the pharmacologicallyacceptable salt thereof as set forth in claim 1, wherein the biphenylcompound is represented by the following formula (II):

wherein R¹, R², R³, R⁴, R⁵ and n are each as defined in claim
 1. 3. Thebiphenyl compound or the pharmacologically acceptable salt thereof asset forth in claim 1, wherein the biphenyl compound is represented bythe following formula (II′):

wherein R¹ represents a hydroxyl group, an amino group, a lower alkoxygroup, a lower alkoxyalkyl group, a lower alkoxyalkoxy group, an arylgroup selected from the group consisting of a phenyl group, a tolylgroup, a xylyl group, a methoxyphenyl group, a chlorophenyl group, abromophenyl group, a fluorophenyl group, a nitrophenyl group and acyanophenyl group, a heteroaryl group selected from the group consistingof a furanyl group, a pyranyl group, and a pyridyl group, a halogenatedheteroarylalkyl group selected from the group consisting of a furfurylgroup, and a pyridylmethyl group, wherein a halogen is attached to theheteroaryl ring, a cyano lower alkyl group, a hydroxy lower alkyl group,a lower alkoxycarbonyl group, a cyano group, a formyl group, a loweracyl group, an aralkylcarbonyl group selected from the group consistingof a benzyl group, a methylbenzyl group, a phenethyl group and aphenylpropyl group to which a carbonyl group is bonded, atetrahydrofuranyl or tetrahydropyranyl group, an alkenyl group, a loweralkylsulfinyl group, a lower alkylsulfonyl group, a loweralkylaminosulfonyl group, an arylaminosulfonyl group selected from thegroup consisting of a phenyl group, a tolyl group, a xylyl group, amethoxyphenyl group, a chlorophenyl group, a bromophenyl group, afluorophenyl group, a nitrophenyl group and a cyanophenyl group to whichan aminosulfonyl group is bonded, a halogenated lower alkylsulfonylaminogroup or an arylsulfonylamino group; R² represents a hydrogen atom, ahalogen atom, a lower alkoxy group or a cyano group; R³ represents ahydrogen atom, a halogen atom, a lower alkyl group, a halogenated loweralkyl group, a lower alkoxy group, a halogenated lower alkoxy group or acyano group; R⁴ represents a hydrogen atom or a halogen atom; R⁵represents a halogenated lower alkyl group, a hydroxy lower alkyl group,a lower alkoxycarbonyl group or an aryloxycarbonyl group selected fromthe group consisting of a phenyl group, a tolyl group, a xylyl group, amethoxyphenyl group, a chlorophenyl group, a bromophenyl group, afluorophenyl group, a nitrophenyl group and a cyanophenyl group to whichthe oxycarbonyl is bonded; and n is
 0. 4. A pharmacological compositionwhich comprises a therapeutically or amelioratively effective amount ofa biphenyl compound or a pharmacologically acceptable salt thereof asset forth in claim 1 and a pharmacologically acceptable vehicle.